Alkoxy substituted imidazoquinolines

ABSTRACT

Imidazoquinoline compounds with an alkoxy substituent at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, intermediates, methods of making, and methods of use of these compounds as immunomodulators, for inducing or inhibiting cytokine biosynthesis in animals and in the treatment of diseases including viral, and neoplastic, are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 14/502,157,filed Sep. 30, 2014, now U.S. Pat. No. 9,365,567, which is acontinuation of application Ser. No. 10/595,230, filed Mar. 28, 2006,now U.S. Pat. No. 8,871,782, which is a National Stage filing ofInternational Application No. PCT/US2004/032616, filed Oct. 1, 2004,which claims priority to U.S. Provisional Patent Application Ser. No.60/508,634, filed on Oct. 3, 2003, each of which is incorporated hereinby reference.

BACKGROUND

In the 1950's the 1H-imidazo[4,5-c]quinoline ring system was developed,and 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline wassynthesized for possible use as an antimalarial agent. Subsequently,syntheses of various substituted 1H-imidazo[4,5-c]quinolines werereported. For example,1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline was synthesized as apossible anticonvulsant and cardiovascular agent. Also, several2-oxoimidazo[4,5-c]quinolines have been reported.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substitutedderivatives thereof were later found to be useful as antiviral agents,bronchodilators and immunomodulators. Subsequently, certain substituted1H-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine,tetrahydroquinolin-4-amine, naphthyridin-4-amine, andtetrahydronaphthyridin-4-amine compounds as well as certain analogousthiazolo and oxazolo compounds were synthesized and found to be usefulas immune response modifiers (IRMs), rendering them useful in thetreatment of a variety of disorders.

There continues to be interest in and a need for compounds that have theability to modulate the immune response, by induction of cytokinebiosynthesis or other mechanisms.

SUMMARY

A new class of compounds useful for modulating cytokine biosynthesis hasnow been found. In one aspect, the present invention provides suchcompounds, which are of Formula I:

wherein R, n, R′, R″, and R₃ are as defined below; and pharmaceuticallyacceptable salts thereof.

The compounds of the present invention are useful as immune responsemodifiers (IRMs) due to their ability to induce or inhibit cytokinebiosynthesis (e.g., induce or inhibit the biosynthesis or production ofone or more cytokines) and otherwise modulate the immune response whenadministered to animals. Compounds can be tested per the test proceduresdescribed in the Examples Section. Compounds can be tested for inductionof cytokine biosynthesis by incubating human peripheral bloodmononuclear cells (PBMC) in a culture with the compound(s) at aconcentration range of 30 to 0.014 μM and analyzing for interferon (α)or tumor necrosis factor (α) in the culture supernatant. Compounds canbe tested for inhibition of cytokine biosynthesis by incubating mousemacrophage cell line Raw 264.7 in a culture with the compound(s) at asingle concentration of, for example, 5 μM and analyzing for tumornecrosis factor (α) in the culture supernatant. The ability to modulatecytokine biosynthesis, for example, induce the biosynthesis of one ormore cytokines, makes the compounds useful in the treatment of a varietyof conditions such as viral diseases and neoplastic diseases, that areresponsive to such changes in the immune response.

In another aspect, the present invention provides pharmaceuticalcompositions containing the immune response modifier compounds, andmethods of inducing or inhibiting cytokine biosynthesis in an animal,treating a viral disease in an animal, and treating a neoplastic diseasein an animal, by administering an effective amount of one or morecompounds of Formula I and/or pharmaceutically acceptable salts thereofto the animal.

In another aspect, the invention provides methods of synthesizingcompounds of Formula I and intermediates useful in the synthesis ofthese compounds.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably.

The terms “comprising” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. Guidance is also provided herein through listsof examples, which can be used in various combinations. In eachinstance, the recited list serves only as a representative group andshould not be interpreted as an exclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention provides such compounds of the following FormulaI:

wherein R, n, R′, R″, and R₃ are as defined below; and pharmaceuticallyacceptable salts thereof.

Examples of compounds of Formula I are more specifically defined by thefollowing Formulas II-VIII:

wherein R, R₁, R₂, R₃₋₁, R₃₋₂, R₃₋₃, R₃₋₄, R₃₋₅, R₃₋₆, and n are asdefined below; and pharmaceutically acceptable salts thereof.

The compounds of Formula VIII and salts thereof are also useful asintermediates for the preparation of compounds and salts of FormulasI-VII. The present invention also provides intermediate compounds ofFormula IX:

wherein R, R₁, R₂, R₃, and n are as defined below.

In one aspect, the present invention provides compounds of the formula(I):

wherein:

R₃ is selected from the group consisting of

-   -   —Z—Y—X—Y—R₄,    -   —Z—R₅,    -   —Z-Het,    -   —Z-Het′-R₄, and    -   —Z-Het′-Y—R₄;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, amino,alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1; and

R′ and R″ are independently selected from the group consisting ofhydrogen and non-interfering substitutents;

with the proviso that Z can also be a bond when:

-   -   R₃ is —Z-Het, —Z-Het′-R₄, or —Z-Het′-Y—R₄; or    -   R₃ is —Z—Y—R₄ or —Z—Y—X—Y—R₄, and Y is selected from —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

or

-   -   R₃ is —Z—R₅ and R₅ is

or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides compounds of theformula (II):

wherein:

R₃ is selected from the group consisting of

-   -   —Z—Y—R₄,    -   —Z—Y—X—Y—R₄,    -   —Z-Het,    -   —Z-Het′-R₄, and    -   —Z-Het′-Y—R₄;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, amino,alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is —Z-Het, —Z-Het′-R₄, or —Z-Het′-Y—R₄; or    -   R₃ is —Z—Y—R₄ or —Z—Y—X—Y—R₄, and Y is selected from —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

or

-   -   R₃ is —Z—R₅ and R₅ is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (III):

wherein:

R₃₋₁ is selected from the group consisting of

-   -   —Z—N(R₈)—C(R₆)—R₄,

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when R₃₋₁ is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (IV):

wherein:

R₃₋₂ is selected from the group consisting of

-   -   —Z—N(R₈)—S(O)₂—R₄,    -   —Z—N(R₈)—S(O)₂—N(R₈)—R₄,

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when R₃₋₂ is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (V):

wherein:

R₃₋₃ is selected from the group consisting of

-   -   —Z—N(R₈)—C(R₆)—N(R₈)—W—R₄,

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when R₃₋₃ is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (VI):

wherein:

R₃₋₄ is selected from the group consisting of

-   -   —Z_(a)—C(R₆)—R₄,    -   —Z_(a)—C(R₆)—O—R₄,    -   —Z_(a)—C(R₆)—N(R₈)—R₄, and

Z_(a) is selected from the group consisting of a bond, alkylene,alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylenecan be optionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—N(R₄)—, and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (VII):

wherein:

R₃₋₅ is selected from the group consisting of

-   -   —Z—N(R₈)—C(R₆)—O—R₄;

and

-   -   —Z—N(R₈)—C(R₆)—C(R₆)—R₄;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when R₃₋₅ is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (VIII):

wherein:

R₃₋₆ is selected from the group consisting of

-   -   —Z—N(R₈)H, and

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when R₃₋₆ is

or a pharmaceutically acceptable salt thereof.

The compounds of Formula VIII and salts thereof are also useful asintermediates for the preparation of compounds and salts of FormulasI-VII.

In another aspect, the present invention provides intermediate compoundsof Formula IX:

wherein:

R₃ is selected from the group consisting of

-   -   —Z—Y—R₄,    -   —Z—Y—X—Y—R₄,    -   —Z-Het,    -   —Z-Het′-R₄, and    -   —Z-Het′-Y—R₄;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₁ is selected from the group consisting of

-   -   —R₄,    -   —X—R₄,    -   —X—Y—X—Y—R₄, and    -   —X—R₅;

R₂ is selected from the group consisting of

-   -   —R₄,    -   —X—Y—R₄, and    -   —X—R₅;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, amino,alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is —Z-Het, —Z-Het′-R₄, or —Z-Het′-Y—R₄; or    -   R₃ is —Z—Y—R₄ or —Z—Y—X—Y—R₄, and Y is selected from —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

or

-   -   R₃ is —Z—R₅ and R₅ is

or a pharmaceutically acceptable salt thereof.

Certain embodiments of the present invention include non-interferingsubstituents. For example, in certain embodiments, R′ and R″ areindependently selected from the group consisting of hydrogen andnon-interfering substitutents.

Herein, “non-interfering” means that the immunomodulator activity (forexample, the ability to induce the biosynthesis of one or more cytokinesor the ability to inhibit the biosynthesis of one or more cytokines) ofthe compound or salt is not destroyed. Illustrative non-interfering R′groups include those described herein for R₁. Illustrativenon-interfering R″ groups include those described herein for R₂.

As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenylgroups containing from 2 to 20 carbon atoms, and alkynyl groupscontaining from 2 to 20 carbon atoms. In some embodiments, these groupshave a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclicor polycyclic and preferably have from 3 to 10 ring carbon atoms.Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl,cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstitutedbornyl, norbornyl, and norbornenyl.

Unless otherwise specified, “alkylene,” “-alkylene-”, “alkenylene”,“-alkenylene-”, “alkynylene”, and “-alkynylene-” are the divalent formsof the “alkyl”, “alkenyl”, and “alkynyl” groups defined above. The terms“alkylenyl”, “alkenylenyl”, and “alkynylenyl” are used when “alkylene”,“alkenylene”, and “alkynylene”, respectively, are substituted. Forexample, an arylalkylenyl group comprises an “alkylene” moiety to whichan aryl group is attached.

The term “haloalkyl” is inclusive of alkyl groups that are substitutedby one or more halogen atoms, including perfluorinated groups. This isalso true of other groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl.

The term “heteroatom” refers to the atoms O, S, or N.

The term “heteroaryl” includes aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N). Suitableheteroaryl groups include furyl, thienyl, pyridyl, quinolinyl,isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl,imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl,purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl,triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.

The term “heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N) and includes all ofthe fully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. Exemplary heterocyclic groups includepyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl(azepanyl), homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl,dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl,dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl,dihydro-1H-imidazolyl, and the like. When “heterocyclyl” contains anitrogen atom, the point of attachment of the heterocyclyl group may bethe nitrogen atom.

The terms “arylene”, “heteroarylene”, and “heterocyclylene” are thedivalent forms of the “aryl”, “heteroaryl”, and “heterocyclyl” groupsdefined above. The terms “arylenyl,” “heteroarylenyl,” and“heterocyclylenyl” are used when “arylene”, “heteroarylene”, and“heterocyclylene”, respectively, are substituted. For example, analkylarylenyl group comprises an arylene moiety to which an alkyl groupis attached.

When a group (or substituent or variable) is present more than once inany Formula described herein, each group (or substituent or variable) isindependently selected, whether explicitly stated or not. For example,for the formula —N(R₈)—C(R₆)—N(R₈)— each R₈ group is independentlyselected. In another example, when an R₂ and an R₃ group both contain anR₄ group, each R₄ group is independently selected. In a further example,when more than one Y group is present (i.e., R₂ and R₃ both contain a Ygroup) and each Y group contains one or more R₈ groups, then each Ygroup is independently selected, and each R₈ group is independentlyselected.

The invention is inclusive of the compounds described herein in any oftheir pharmaceutically acceptable forms, including isomers (e.g.,diastereomers and enantiomers), salts, solvates, polymorphs, and thelike. In particular, if a compound is optically active, the inventionspecifically includes each of the compound's enantiomers as well asracemic mixtures of the enantiomers. It should be understood that theterm “compound” includes any or all of such forms, whether explicitlystated or not (although at times, “salts” are explicitly stated).

For any of the compounds presented herein, each one of the followingvariables (e.g., R, R′, R″, R₁, R₂, R₃, n, A, X, Z, and so on) in any ofits embodiments can be combined with any one or more of the othervariables in any of their embodiments as would be understood by one ofskill in the art. Each of the resulting combinations of variables is anembodiment of the present invention.

In some embodiments, compounds of Formula I-VIII induce the biosynthesisof one or more cytokines.

In some embodiments, compounds of Formula I-VIII inhibit thebiosynthesis of one or more cytokines (e.g., TNF-α).

In certain embodiments, R is selected from the group consisting ofalkyl, alkoxy, hydroxy, halogen, and trifluoromethyl.

In some embodiments of Formula I, R′ is selected from the groupconsisting of —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄, and —X—R₅.

In some embodiments, R′ is selected from the group consisting of alkyl,arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, dihydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R₄, —X—R₅, and heterocyclylalkylenyl, whereinthe heterocyclyl of the heterocyclylalkylenyl group is optionallysubstituted by one or more alkyl groups; wherein X is alkylene; Y is—N(R₈)—C(O)—, —N(R₈)—S(O)₂—, —N(R₈)—C(O)—N(R₈)—, or

R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In certain embodiments, R′ is selected from the group consisting ofalkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R₄, and —X—R₅; wherein X is alkylene; Y is—N(R₈)—C(O)—, —N(R₈)—S(O)₂—, —N(R₈)—C(O)—N(R₈)—, or

R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In some embodiments of Formula I, R″ is selected from the groupconsisting of —R₄, —X—R₄, —X—Y—R₄, and —X—R₅. In some embodiments, R″ isselected from the group consisting of hydrogen, alkyl, andalkoxyalkylenyl. In some embodiments, R″ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.

In some embodiments, R₁ is selected from the group consisting of —R₄,—X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄, and —X—R₅.

In some embodiments (e.g., of Formulas II-IX), R₁ is selected from thegroup consisting of alkyl, arylalkylenyl, aryloxyalkylenyl,hydroxyalkyl, dihydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R₄, —X—R₅,and heterocyclylalkylenyl, wherein the heterocyclyl of theheterocyclylalkylenyl group is optionally substituted by one or morealkyl groups; wherein X is alkylene; Y is —N(R₈)—C(O)—, —N(R₈)—S(O)₂—,—N(R₈)—C(O)—N(R₈)—, or

R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In certain embodiments, R₁ is selected from the group consisting ofalkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R₄, and —X—R₅; wherein X is alkylene; Y is—N(R₈)—C(O)—, —N(R₈)—S(O)₂—, —N(R₈)—C(O)—N(R₈)—, or

R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In some embodiments (e.g., of Formulas II-IX), R₁ is selected from thegroup consisting of methyl, n-propyl, 2-methylpropyl, 2-phenylethyl,2-phenoxyethyl, benzyl, 4-(methanesulfonylamino)butyl,2-(methanesulfonylamino)-2-methylpropyl, 4-(benzenesulfonylamino)butyl,2-(acetamido)-2-methylpropyl, 4-(ureido)butyl, 2-hydroxy-2-methylpropyl,5-(methanesulfonyl)pentyl, 4-aminobutyl, 4-(3-phenylureido)butyl,4-(benzoylamino)lbutyl, 4-[(4-morpholinecarbonyl)amino]butyl,2-(1,1-dioxidoisothiazolidin-2-yl)ethyl,3-(1,1-dioxidoisothiazolidin-2-yl)propyl,4-(1,1-dioxidoisothiazolidin-2-yl)butyl,2-(benzoylamino)-2-methylpropyl, 2-(3-phenylureido)butyl,2-(2-oxopyrrolidin-1-yl)ethyl, 3-(2-oxopyrrolidin-1-yl)propyl,4-(2-oxopyrrolidin-1-yl)butyl.

In some embodiments (e.g., of Formulas II-IX), R₁ is selected from thegroup consisting of 2-hydroxy-2-methylpropyl, 2-methylpropyl, propyl,ethyl, methyl, 2,3-dihydroxypropyl, 2-phenoxyethyl, 4-[(methylsulfonyl)amino]butyl, 2-methyl-2-[(methyl sulfonyl)amino]propyl,2-(acetylamino)-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl,4-{[(isopropylamino)carbonyl]amino}butyl,4-(1,1-dioxidoisothiazolidin-2-yl)butyl, tetrahydro-2H-pyran-4-ylmethyl,and (2,2-dimethyl-1,3-dioxolan-4-yl)methyl.

In some embodiments, R₂ is selected from the group consisting of —R₄,—X—R₄, —X—Y—R₄, and —X—R₅.

In some embodiments (e.g., of Formulas II-IX), R₂ is selected from thegroup consisting of hydrogen, alkyl, alkoxyalkylenyl, andhydroxyalkylenyl. In some embodiments (e.g., of Formulas II-IX), R₂ isselected from the group consisting of hydrogen, alkyl, andalkoxyalkylenyl. In some embodiments, R₂ is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl,methoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.

In some embodiments (e.g., of Formulas II-X), R₂ is selected from thegroup consisting of methyl, ethyl, n-propyl, n-butyl, ethoxymethyl,methoxyethyl, methoxymethyl, hydrogen, hydroxymethyl,2-methoxy(ethoxymethyl), 4-(3-phenylureido)butyl, cyclopropylmethyl,trifluoromethyl, phenyl, and benzyl.

In certain embodiments of the present invention, R₃ is selected from thegroup consisting of —Z—Y—R₄, —Z—Y—X—Y—R₄, —Z—R₅, —Z-Het, —Z-Het′-R₄, and—Z-Het′-Y—R₄. In some embodiments (e.g., of Formulas I or II), R₃ is—Z—Y—R₄ or —Z—Y—X—Y—R₄. In some embodiments (e.g., of Formula I or II),R₃ is —Z—R₅. In some embodiments (e.g., of Formula I or II), R₃ is—Z-Het, —Z-Het′-R₄, or —Z-Het′-Y—R₄.

In certain embodiments, R₃ is —Z—Y—R₄ or —Z—Y—X—Y—R₄, wherein Y isselected from the group consisting of —S(O)₀₋₂—, —C(O)—, —C(O)—O—,—O—C(O)—, —C(R₆)—N(R₈),

wherein Q is selected from the group consisting of a bond, —C(O)—,—C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—W—, and —S(O)₂—N(R₈)—; W is selectedfrom the group consisting of a bond, —C(O)—, and —S(O)₂—; R₆ is selectedfrom the group consisting of ═O or ═S; R₈ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and alkoxyalkylenyl; and R₁₀ isselected from the group consisting of C₄₋₆ alkylene; X is selected fromthe group consisting of alkylene, arylene, heterocyclylene,heteroarylene, and alkylene terminated with heteroarylene; and R₄ isselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl,aryloxyalkylenyl, heteroaryl, and heterocyclyl, wherein alkyl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of hydroxy, alkoxy, and heterocyclyl, and whereinarylalkylenyl and heteroarylalkylenyl are unsubstituted or substitutedby one or more substituents selected from the group consisting of alkyl,halogen, and alkoxy.

In certain embodiments, R₃ is —Z—Y—R₄ or —Z—Y—X—Y—R₄. In certain ofthese embodiments, Y is selected from the group consisting of —S(O)₀₋₂—,—C(O)—, —C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈),

wherein Q is selected from the group consisting of a bond, —C(O)—,—C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—W—, and —S(O)₂—N(R₈)—; W is selectedfrom the group consisting of a bond, —C(O)—, and —S(O)₂—; R₆ is selectedfrom the group consisting of ═O and ═S; R₈ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and alkoxyalkylenyl; and R₁₀ is aC₄₋₆ alkylene.

In some embodiments (e.g., of Formula II), R₃ is —Z—R₅, wherein R₅ isselected from the group consisting of

whereinR₇ is C₃₋₅ alkylene; R₁₀ is C₄₋₆ alkylene; and a and b are eachindependently 1 to 3.

In some embodiments (e.g., of Formula II), R₃ is —Z-Het, —Z-Het′-R₄, or—Z-Het′-Y—R₄. In certain of these embodiments, Het is substituted by oneor more substituents selected from the group consisting of alkyl,hydroxy, hydroxyalkyl, hydroxyalkyleneoxylalkylenyl, diakylamino, andheterocyclyl. In certain of these embodiments, Y is selected from thegroup consisting of —C(O)—, —C(O)—O—, —C(O)—N(H)—, and —N(H)—C(O)—. Incertain embodiments, Het or Het′ is selected from the group consistingof tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, aziridinyl,azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl. Incertain embodiments Het is selected from the group consisting oftetrahydropyranyl and tetrahydrofuranyl.

In some embodiments of Formula III, R₃₋₁ is selected from the groupconsisting of —Z—N(R₈)—C(R₆)—R₄,

In some embodiments of Formula III, R₃₋₁ is —Z—N(R₈)—C(R₆)—R₄. Incertain embodiments of this formula for R₃₋₁, Z is C₂₋₆ alkylene. Incertain embodiments of this, R₈ is hydrogen, R₆ is ═O, and R₄ isselected from the group consisting of alkyl, alkenyl, aryl,arylalkylenyl, aryloxyalkylenyl, and heteroaryl wherein the alkyl,alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groupscan be unsubstituted or substituted by one or more substituents selectedfrom the group consisting of alkyl, aryl, halogen, alkoxy, cyano,arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl,trifluoromethyl, trifluoromethoxy, and in the case of alkyl, oxo. Incertain embodiments of this, R₈ is hydrogen, R₆ is ═O, and R₄ isselected from the group consisting of alkyl, alkenyl, aryl,arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein aryl can beoptionally substituted with halogen, methoxy, cyano, trifluoromethyl,and trifluoromethoxy. In certain embodiments, Z is ethylene orpropylene, R₈ is hydrogen, R₆ is ═O, and R₄ is C₁₋₃ alkyl.

In some embodiments of Formula III, R₃₋₁ is

In certain embodiments of this formula for R₃₋₁, Z is a bond. In certainembodiments of this, R₆ is ═O, R₁₀ is C₄₋₆ alkylene, and R₄ is selectedfrom the group consisting of alkyl, alkenyl, aryl, arylalkylenyl,aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl,arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can beunsubstituted or substituted by one or more substituents selected fromthe group consisting of alkyl, aryl, halogen, alkoxy, cyano,arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl,trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo. Incertain embodiments, R₄ is alkyl or aryl.

In certain embodiments, R₃₋₁ is

In some embodiments of Formula III, R₃₋₁ is

In certain embodiments of this formula for R₃₋₁, R₆ is ═O, and R₇ isC₃₋₅ alkylene. In certain of these embodiments, Z is ethylene orpropylene and R₇ is propylene.

In some embodiments of Formula IV, R₃₋₂ is selected from the groupconsisting of —Z—N(R₈)—S(O)₂—R₄, —Z—N(R₈)—S(O)₂—N(R₈)—R₄,

In some embodiments of Formula IV, R₃₋₂ is —Z—N(R₈)—S(O)₂—R₄. In certainembodiments of this formula for R₃₋₂, R₈ is hydrogen, and R₄ is selectedfrom the group consisting of alkyl, alkenyl, aryl, arylalkylenyl,aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl,arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can beunsubstituted or substituted by one or more substituents selected fromthe group consisting of alkyl, aryl, halogen, alkoxy, cyano,arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl,trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo. Incertain embodiments, R₄ is selected from the group consisting of alkyl,aryl, alkenyl, heteroaryl, arylalkylenyl, and alkylheteroarylenyl;wherein aryl can be optionally substituted with halogen, methoxy, cyano,trifluoromethyl, and trifluoromethoxy. In certain embodiments, Z isethylene or propylene, R₈ is hydrogen, and R₄ is C₁₋₃ alkyl.

In some embodiments of Formula IV, R₃₋₂ is

In certain embodiments of this formula for R₃₋₂, R₇ is C₃₋₅ alkylene.

In some embodiments of Formula IV, R₃₋₂ is

In certain embodiments of this formula for R₃₋₂, Z is a bond. In certainembodiments of this formula for R₃₋₂, R₁₀ is C₄₋₆ alkylene, and R₄ isselected from the group consisting of alkyl, alkenyl, aryl,arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl,alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groupscan be unsubstituted or substituted by one or more substituents selectedfrom the group consisting of alkyl, aryl, halogen, alkoxy, cyano,arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl,trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo. Incertain of these embodiments, R₄ is selected from the group consistingof alkyl, aryl, heteroaryl, arylalkylenyl, and alkylheteroarylenyl,wherein aryl can be optionally substituted with halogen, methoxy, cyano,trifluoromethyl, trifluoromethoxy.

In certain embodiments, R₃₋₂ is

In some embodiments of Formula IV, R₃₋₂ is —Z—N(R₈)—S(O)₂—N(R₈)—R₄ or

In certain embodiments of this formula for R₃₋₂, R₁₀ is C₄₋₆ alkylene,R₈ is hydrogen or C₁₋₄ alkyl, and R₄ is alkyl.

In certain embodiments R₃₋₂ is

and Z is a bond.

In some embodiments, R₃₋₃ is selected from the group consisting of—Z—N(R₈)—C(R₆)—N(R₈)—W—R₄,

In some embodiments of Formula V, R₃₋₃ is —Z—N(R₈)—C(R₆)—N(R₈)—W—R₄. Incertain embodiments of this formula for R₃₋₃, R₆ is ═O or ═S, R₈ ishydrogen or C₁₋₄ alkyl, W is a bond, —C(O)—, or —S(O)₂—; and R₄ isselected from the group consisting of alkyl, alkenyl, aryl,arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl,alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groupscan be unsubstituted or substituted by one or more substituents selectedfrom the group consisting of alkyl, aryl, halogen, alkoxy, cyano,arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl,trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo. Incertain embodiments, R₄ is selected from the group consisting of alkyl,aryl, arylalkylenyl, and heteroaryl; wherein aryl can be optionallysubstituted with halogen, methoxy, cyano, trifluoromethyl, andtrifluoromethoxy. In certain embodiments, Z is ethylene or propylene,each R₈ is hydrogen, R₆ is ═O, and R₄ is isopropyl.

In some embodiments of Formula V, R₃₋₃ is

In certain embodiments of this formula for R₃₋₃, R₆ is ═O, R₈ ishydrogen, a and b are each independently 1 to 3, and A is —O—. Incertain of these embodiments, Z is ethylene or propylene, and a and bare each 2.

In some embodiments of Formula V, R₃₋₃ is

In certain embodiments of this formula for R₃₋₃, R₆ is ═O, R₁₀ is C₄₋₆alkylene, a and b are each independently 1 to 3, and A is —O—. Incertain embodiments, Z is a bond.

In certain embodiments, R₃₋₃ is

In some embodiments of Formula V, R₃₋₃ is

In certain embodiments of this formula for R₃₋₃, R₆ is ═O or ═S, R₈ ishydrogen or C₁₋₄ alkyl, R₁₀ is C₄₋₆ alkylene, W is a bond, —C(O)—, or—S(O)₂—, and R₄ is selected from the group consisting of alkyl, alkenyl,aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein thealkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroarylgroups can be unsubstituted or substituted by one or more substituentsselected from the group consisting of alkyl, aryl, halogen, alkoxy,cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl,trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo. Incertain embodiments W is a bond or —C(O)—. In certain embodiments, R₄ isselected from the group consisting of alkyl, aryl, arylalkylenyl, andheteroaryl; wherein aryl can be optionally substituted with halogen,methoxy, cyano, trifluoromethyl, and trifluoromethoxy. In certainembodiments, Z is a bond.

In certain embodiments, R₃₋₃ is

In some embodiments of Formula V, R₃₋₃ is

In certain embodiments of this formula for R₃₋₃, R₆ is ═O or ═S, R₈ ishydrogen or C₁₋₄ alkyl, R₁₀ is C₄₋₆ alkylene, and R₄ is hydrogen oralkyl.

In some embodiments of Formula V, R₃₋₃ is

In certain embodiments of this formula for R₃₋₃, R₆ is ═O or ═S, R₁₀ isC₄₋₆ alkylene, and R₄ is hydrogen or alkyl. In certain embodiments, Z isa bond.

In some embodiments of Formula V, R₃₋₃ is

In certain embodiments of this formula for R₃₋₃, R₆ is ═O or ═S, R₇ isC₂₋₄ alkylene, W is a bond, and R₄ is hydrogen or alkyl.

In some embodiments of Formula VI, R₃₋₄ is —Z_(a)—C(R₆)—R₄,—Z_(a)—C(R₆)—O—R₄, —Z_(a)—C(R₆)—N(R₈)—R₄, or

In some embodiments of Formula VI, R₃₋₄ is —Z_(a)—C(R₆)—R₄. In certainembodiments of this formula for R₃₋₄, R₆ is ═O or ═S, and R₄ is alkyl,aryl, or heterocyclyl.

In some embodiments of Formula VI, R₃₋₄ is —Z_(a)—C(R₆)—O—R₄. In certainembodiments of this formula for R₃₋₄, R₆ is ═O and R₄ is hydrogen oralkyl.

In some embodiments of Formula VI, R₃₋₄ is —Z_(a)—C(R₆)—N(R₈)—R₄. Incertain embodiments of this formula for R₃₋₄, R₆ is ═O or ═S, R₈ ishydrogen, alkyl, or alkoxyalkylenyl, and R₄ is alkyl, aryl, orarylalkylenyl; wherein aryl can be optionally substituted with halogen,methoxy, cyano, trifluoromethyl, and trifluoromethoxy.

In some embodiments of Formula VI, R₃₋₄ is

In certain embodiments of this formula for R₃₋₄, R₆ is ═O or ═S, a and bare each independently 1 to 3, and A′ is selected from the groupconsisting of —CH₂—, —S(O)₂—, and —O—. In certain embodiments A′ is—CH₂—. In certain of these embodiments, Z_(a) is methylene, R₆ is ═O, ais 1 or 2, b is 2, and A′ is —CH₂—. In certain of these embodiments,Z_(a) is methylene, R₆ is ═O, a and b are each 2, and A′ is —O—.

In certain embodiments of Formula VI, Z_(a) is a bond or alkylene.

In some embodiments of Formula VII, R₃₋₅ is —Z—N(R₈)—C(R₆)—O—R₄,

or —Z—N(R₈)—C(R₆)—C(R₆)—R₄.

In some embodiments of Formula VII, R₃₋₅ is —Z—N(R₈)—C(R₆)—O—R₄. Incertain embodiments of this formula for R₃₋₅, R₆ is ═O, R₈ is hydrogen,and R₄ is alkyl.

In some embodiments of Formula VII, R₃₋₅ is

In certain embodiments of this formula for R₃₋₅, R₆ is ═O, R₁₀ is C₄₋₆alkylene, and R₄ is alkyl. In certain embodiments, Z is a bond.

In some embodiments of Formula VII, R₃₋₅ is —Z—N(R₈)—C(R₆)—C(R₆)—R₄. Incertain embodiments of this formula for R₃₋₅, R₆ is ═O or ═S, R₈ ishydrogen, and R₄ is alkyl, aryl, or heteroaryl; wherein aryl can beoptionally substituted with halogen, methoxy, cyano, trifluoromethyl,and trifluoromethoxy.

In some embodiments of Formula VIII, R₃₋₆ is —Z—N(R₈)H or

In some embodiments of Formula VIII, R₃₋₆ is —Z—N(R₈)H. In certainembodiments of this formula for R₃₋₆, Z is alkylene, and R₈ is hydrogen.

In some embodiments of Formula VIII, R₃₋₆ is

In certain embodiments of this formula for R₃₋₆, Z is a bond, and R₁₀ isC₄₋₆ alkylene.

In certain embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo.

In certain embodiments, R₄ is selected from the group consisting ofalkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl,wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, andheteroaryl groups can be unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, halogen,alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy,heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case ofalkyl, oxo.

In certain embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, aryl, arylalkylenyl, alkylheteroarylenyl,heteroarylalkylenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl,wherein alkyl is unsubstituted or substituted by one or moresubstituents selected from the group consisting of hydroxy, alkoxy, andheterocyclyl, and wherein arylalkylenyl and heteroarylalkylenyl areunsubstituted or substituted by one or more substituents selected fromthe group consisting of alkyl, halogen, and alkoxy.

In certain embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, aryl, arylalkylenyl, alkylheteroarylenyl,heteroarylalkylenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl.

In certain embodiments, R₄ is selected from the group consisting ofhydrogen and alkyl. In certain embodiments, R₄ is alkyl. In certainembodiments, R₄ is alkyl or aryl. In certain embodiments, R₄ is C₁₋₃alkyl. In certain embodiments, R₄ is isopropyl.

In certain embodiments, R₄ is alkyl, aryl, or heterocyclyl. In certainembodiments, R₄ is alkyl, aryl, or heteroaryl, wherein aryl can beoptionally substituted with halogen, methoxy, cyano, trifluoromethyl,and trifluoromethoxy.

In certain embodiments, R₄ is selected from the group consisting ofalkyl, aryl, alkenyl, heteroaryl, arylalkylenyl, andalkylheteroarylenyl; wherein aryl can be optionally substituted withhalogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R₄ is alkyl, aryl, or arylalkylenyl; whereinaryl can be optionally substituted with halogen, methoxy, cyano,trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R₅ is selected from the group consisting of

In certain embodiments, R₅ is selected from the group consisting of

In certain of these embodiments, R₇ is C₃₋₅ alkylene; R₁₀ is C₄₋₆alkylene; and a and b are each independently 1 to 3.

In certain embodiments, R₆ is selected from the group consisting of ═Oand ═S. In certain embodiments, R₆ is ═O.

In certain embodiments, R₇ is a C₂₋₇ alkylene. In certain embodiments,R₇ is C₃₋₅ alkylene. In certain embodiments, R₇ is C₂₋₄ alkylene. Incertain embodiments, R₇ is propylene.

In certain embodiments, R₈ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl. In certainembodiments, R₈ is selected from the group consisting of hydrogen, C₁₋₄alkyl, and alkoxyalkylenyl. In certain embodiments, R₈ is hydrogen orC₁₋₄ alkyl. In certain embodiments, R₈ is hydrogen.

In certain embodiments, R₉ is selected from the group consisting ofhydrogen and alkyl.

In certain embodiments, R₁₀ is a C₃₋₈ alkylene. In certain embodiments,R₁₀ is a C₄₋₆ alkylene. In certain embodiments, R₁₀ is butylene.

In certain embodiments, A is selected from the group consisting of —O—,—C(O)—, —S(O)₀₋₂—, and —N(R₄)—. In certain embodiments, A is —O—.

In certain embodiments, A′ is selected from the group consisting of —O—,—C(O)—, —S(O)₀₋₂—, —N(R₄)—, and —CH₂—. In certain embodiments, A′ isselected from the group consisting of —CH₂—, —S(O)₂—, and —O—. Incertain embodiments, A′ is —CH₂—. In certain embodiments, A′ is —O—.

In certain embodiments, Q is selected from the group consisting of abond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,—C(R₆)—O—, and —C(R₆)—N(OR₉)—. In certain embodiments, Q is selectedfrom the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O)₂—,—C(R₆)—N(R₈)—W—, and —S(O)₂—N(R₈)—.

In certain embodiments, V is selected from the group consisting of—C(R₆)—, —O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—. In certain embodiments,V is selected from the group consisting of —C(O)— and —N(R₈)—C(O)—.

In certain embodiments, W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—. In certain embodiments, W is a bond or—C(O)—. In certain embodiments, W is a bond.

In certain embodiments, X is selected from the group consisting ofalkylene, alkenylene, alkynylene, arylene, heteroarylene, andheterocyclylene wherein the alkylene, alkenylene, and alkynylene groupscan be optionally interrupted or terminated with arylene, heteroarylene,or heterocyclylene, and optionally interrupted by one or more —O—groups.

In certain embodiments, X is selected from the group consisting ofalkylene, arylene, heterocyclylene, heteroarylene, and alkyleneterminated with heteroarylene. In certain embodiments, X is selectedfrom the group consisting of alkylene, arylene, heteroarylene, andalkylene terminated with heteroarylene.

In certain embodiments, Y is selected from the group consisting of

—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

In certain embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —C(O)—, —C(O)—O—, —O—C(O)—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,

wherein Q is selected from the group consisting of a bond,—C(O)—, —C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—W—, and —S(O)₂—N(R₈)—; W isselected from the group consisting of a bond, —C(O)—, and —S(O)₂—; R₆ isselected from the group consisting of ═O or ═S; R₈ is selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, and alkoxyalkylenyl; and R₁₀is selected from the group consisting of C₄₋₆ alkylene; X is selectedfrom the group consisting of alkylene, arylene, heterocyclylene,heteroarylene, and alkylene terminated with heteroarylene; and R₄ isselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl,aryloxyalkylenyl, heteroaryl, and heterocyclyl, wherein alkyl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of hydroxy, alkoxy, and heterocyclyl, and whereinarylalkylenyl and heteroarylalkylenyl are unsubstituted or substitutedby one or more substituents selected from the group consisting of alkyl,halogen, and alkoxy.

In certain embodiments, Y is selected from the group consisting of

—S(O)₀₋₂—, —C(O)—, —C(O)—O—, —O—C(O)—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,

In certain of these embodiments, Q is selected from the group consistingof a bond, —C(O)—, —C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—W—, and—S(O)₂—N(R₈)—; W is selected from the group consisting of a bond,—C(O)—, and —S(O)₂—; R₆ is selected from the group consisting of ═O or═S; R₈ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,and alkoxyalkylenyl; and R₁₀ is selected from the group consisting ofC₄₋₆ alkylene.

In certain embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —C(O)—, —C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈),

In certain embodiments, Y is selected from the group consisting of—C(O)—, —C(O)—O—, —C(O)—N(H)—, and —N(H)—C(O)—.

In certain embodiments, Z is selected from the group consisting ofalkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, andalkynylene can be optionally interrupted with one or more —O— groups. Zcan also be a bond. In some embodiments (e.g., of Formulas I-IX), Z isalkylene. In certain of these embodiments, Z is C₂₋₆ alkylene. Incertain embodiments Z is ethylene or propylene.

In certain embodiments, Z is a bond. For example, Z can be a bond when:R₃ is —Z-Het, —Z-Het′-R₄, or —Z-Het′-Y—R₄; or R₃ is —Z—Y—R₄ or—Z—Y—X—Y—R₄, and Y is selected from —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—,—C(R₆)—O—, —C(R₆)—N(R₈)—,

or R₃ is —Z—R₅ and R₅ is

As another example, Z can be a bond when R₃₋₁ is

As another example, Z can be a bond when R₃₋₂ is

As another example, Z can be a bond when R₃₋₃ is

As another example, Z can be a bond when R₃₋₅ is

As another example, Z can be a bond when R₃₋₆ is

As another example, Z can be a bond when R₃ is —Z—S(O)₂—CH₃ or—Z—C(O)—NH—CH(CH₃)₂.

In certain embodiments, Z_(a) is selected from the group consisting of abond, alkylene, alkenylene, and alkynylene, wherein alkylene,alkenylene, and alkynylene can be optionally interrupted with one ormore —O— groups. In certain embodiments, Z_(a) is a bond or alkylene. Incertain of these embodiments, Z_(a) is C₁₋₄ alkylene. In certainembodiments, Z_(a) is methylene.

In certain embodiments, Het is heterocyclyl which can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy,heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo. In certain embodiments, Het issubstituted by one or more substituents selected from the groupconsisting of alkyl, hydroxy, hydroxyalkyl,hydroxyalkyleneoxylalkylenyl, diakylamino, and heterocyclyl. In certainembodiments, Het is selected from the group consisting oftetrahydropyranyl and tetrahydrofuranyl.

In certain embodiments, Het is heterocyclyl which can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy,heteroaryloxy, heteroarylalkyleneoxy, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo.

In certain embodiments, Het′ is heterocyclylene which can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano,aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, amino,alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo.

In certain embodiments, Het or Het′ is selected from the groupconsisting of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,aziridinyl, azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl.

In certain embodiments, Het is substituted by one or more substituentsselected from the group consisting of alkyl, hydroxy, hydroxyalkyl,hydroxyalkyleneoxylalkylenyl, diakylamino, and heterocyclyl; Y isselected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—N(H)—, and—N(H)—C(O)—; and R₄ is selected from the group consisting of hydrogenand alkyl.

In some embodiments of Formulas I-IX, R₃—O—, R₃₋₁—O—, R₃₋₂—O—, R₃₋₃—O—,R₃₋₄—O—, R₃₋₅—O—, or R₃₋₆—O— is at the 7- or 8-position. In someembodiments of Formulas I-IX, R₃—O—, R₃₋₁—O—, R₃₋₂—O—, R₃₋₃—O—, R₃₋₄—O—,R₃₋₅—O—, or R₃₋₆—O— at the 7-position. In some embodiments of FormulasI-IX, R₃—O—, R₃₋₁—O—, R₃₋₂—O—, R₃₋₃—O—, R₃₋₄—O—, R₃₋₅—O—, or R₃₋₆—O— isat the 8-position.

In certain embodiments, a and b are independently integers from 1 to 6with the proviso that a+b is ≦7. In certain embodiments, a and b areeach independently 1 to 3. In certain embodiments, a is 1 or 2, and b is2. In certain embodiments, a and b are each 2.

In certain embodiments, n is 0 or 1. In some embodiments (e.g., ofFormulas I-IX), n is 0.

Preparation of the Compounds

Compounds of the invention can be prepared according to Reaction SchemeI where R, R₁, R₂, R₃, and n are as defined above. In step (1) ofReaction Scheme I, a benzyloxyaniline of Formula XV is treated with thecondensation product generated from 2,2-dimethyl-1,3-dioxane-4,6-dione(Meldrum's acid) and triethyl orthoformate to provide an imine ofFormula XVI. The reaction is conveniently carried out by adding asolution of a benzyloxyaniline of Formula XV to a heated mixture ofMeldrum's acid and triethyl orthoformate and heating the reaction at anelevated temperature such as 45° C. The product can be isolated usingconventional methods.

In step (2) of Reaction Scheme I, an imine of Formula XVI undergoesthermolysis and cyclization to provide a benzyloxyquinolin-4-ol ofFormula XVII. The reaction is conveniently carried out in medium such asDOWTHERM A heat transfer fluid at a temperature between 200 and 250° C.The product can be isolated using conventional methods.

In step (3) of Reaction Scheme I, the benzyloxyquinolin-4-ol of FormulaXVII is nitrated under conventional nitration conditions to provide abenzyloxy-3-nitroquinolin-4-ol of Formula XVIII. The reaction isconveniently carried out by adding nitric acid to thebenzyloxyquinolin-4-ol of Formula XVII in a suitable solvent such aspropionic acid and heating the mixture at an elevated temperature suchas 125° C. The product can be isolated using conventional methods.

In step (4) of Reaction Scheme I, a benzyloxy-3-nitroquinolin-4-ol ofFormula XVIII is chlorinated using conventional chlorination chemistryto provide a benzyloxy-4-chloro-3-nitroquinoline of Formula XIX. Thereaction is conveniently carried out by treating thebenzyloxy-3-nitroquinolin-4-ol of Formula XVIII with phosphorousoxychloride in a suitable solvent such as N,N-dimethylformamide (DMF).The reaction can be carried out at an elevated temperature such as 100°C., and the product can be isolated using conventional methods.

In step (5) of Reaction Scheme I, a benzyloxy-4-chloro-3-nitroquinolineof Formula XIX is treated with an amine of Formula R₁—NH₂ to provide abenzyloxy-3-nitroquinolin-4-amine of Formula XX. The reaction isconveniently carried out by adding the amine of Formula R₁—NH₂ to asolution of the benzyloxy-4-chloro-3-nitroquinoline of Formula XIX in asuitable solvent such as dichloromethane or methanol in the presence ofa tertiary amine such as triethylamine. The reaction can be carried outat ambient temperature or at an elevated temperature such as, forexample, the reflux temperature of the solvent. The reaction product canbe isolated using conventional methods. Several amines of Formula R₁—NH₂are commercially available; others can be prepared by known syntheticmethods. For example, methyl tetrahydro-2H-pyran-4-carboxylate treatedwith ammonium hydroxide to form tetrahydro-2H-pyran-4-carboxamide, whichcan then be reduced with lithium aluminum hydride to providetetrahydro-2H-pyran-4-ylmethylamine.

In step (6) of Reaction Scheme I, a benzyloxy-3-nitroquinolin-4-amine ofFormula XX is reduced to provide a benzyloxyquinoline-3,4-diamine ofFormula XXI. The reaction can be carried out by hydrogenation using aheterogeneous hydrogenation catalyst such as platinum on carbon. Thehydrogenation is conveniently carried out in a Parr apparatus in asuitable solvent such as toluene, methanol, or acetonitrile. Thereaction can be carried out at ambient temperature, and the product canbe isolated using conventional methods.

Alternatively, the reduction in step (6) can be carried out using nickelboride, prepared in situ from sodium borohydride and nickel(II)chloride. The reduction is conveniently carried out by adding a solutionof the benzyloxy-3-nitroquinolin-4-amine of Formula XX in a suitablesolvent or solvent mixture such as dichloromethane/methanol to a mixtureof excess sodium borohydride and catalytic nickel(II) chloride inmethanol. The reaction can be carried out at ambient temperature. Theproduct can be isolated using conventional methods.

In step (7) of Reaction Scheme I, a benzyloxyquinoline-3,4-diamine ofFormula XXI is treated with a carboxylic acid equivalent to provide abenzyloxy-1H-imidazo[4,5-c]quinoline of Formula XXII. Suitablecarboxylic acid equivalents include orthoesters of FormulaR₂C(O-alkyl)₃, 1,1-dialkoxyalkyl alkanoates of FormulaR₂C(O-alkyl)₂(O—C(O)-alkyl), and acid chlorides of Formula R₂C(O)Cl. Theselection of the carboxylic acid equivalent is determined by the desiredsubstituent at R₂. For example, triethyl orthoformate will provide acompound where R₂ is hydrogen, and trimethyl orthovalerate will providea compound where R₂ is a butyl group. The reaction is convenientlycarried out by adding the carboxylic acid equivalent to abenzyloxyquinoline-3,4-diamine of Formula XXI in a suitable solvent suchas toluene or xylenes. Optionally, catalytic pyridine hydrochloride canbe added. The reaction is carried out at a temperature high enough todrive off alcohol or water formed during the reaction. Conveniently, aDean-Stark trap can be used to collect the volatiles.

Alternatively, step (7) can be carried out in two steps when an acidchloride of Formula R₂C(O)Cl is used as the carboxylic acid equivalent.Part (i) of step (7) is conveniently carried out by adding the acidchloride to a solution of a benzyloxyquinoline-3,4-diamine of FormulaXXI in a suitable solvent such as dichloromethane or acetonitrile toafford an amide. Optionally, a tertiary amine such as triethylamine,pyridine, or 4-dimethylaminopyridine can be added. The reaction can becarried out at ambient temperature or at an elevated temperature. Theamide product can be isolated and optionally purified using conventionaltechniques. Part (ii) of step (7) involves heating the amide prepared inpart (i) to provide a benzyloxy-1H-imidazo[4,5-c]quinoline of FormulaXXII. The reaction is conveniently carried out in a suitable solventsuch as toluene at a temperature sufficient to drive off water formedduring the reaction. The reaction can also be carried out in a solventsuch as ethanol or methanol in the presence of a base such astriethylamine. The benzyloxy-1H-imidazo[4,5-c]quinoline of Formula XXIIcan be isolated using conventional methods.

In step (8) of Reaction Scheme I, the benzyl group of abenzyloxy-1H-imidazo[4,5-c]quinoline of Formula XXII is cleaved toprovide a 1H-imidazo[4,5-c]quinolinol of Formula XXIII. The cleavage isconveniently carried out on a Parr apparatus under hydrogenolysisconditions using a suitable heterogeneous catalyst such as palladium oncarbon in a solvent such as ethanol. Alternatively, the reaction can becarried out by transfer hydrogenation in the presence of a suitablehydrogenation catalyst. The transfer hydrogenation is convenientlycarried out by adding ammonium formate to a solution of abenzyloxy-1H-imidazo[4,5-c]quinoline of Formula XXII in a suitablesolvent such as ethanol in the presence of a catalyst such as palladiumon carbon. The reaction is carried out at an elevated temperature, forexample, the refluxing temperature of the solvent. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

In step (9) of Reaction Scheme I a 1H-imidazo[4,5-c]quinolinol ofFormula XXIII is converted to an ether-substituted1H-imidazo[4,5-c]quinoline of Formula IX using a Williamson-type ethersynthesis. The reaction is effected by treating a1H-imidazo[4,5-c]quinolinol of Formula XXIII with an alkyl halide ofFormula Halide-Z—Y—R₄, Halide-Z—R₅, Halide-Z—Y—X—Y—R₄, or Halide-Z-Het,wherein Z, Y, X, R₄, R₅, and Het are as defined above, in the presenceof a base. The reaction is conveniently carried out by combining thealkyl halide with a 1H-imidazo[4,5-c]quinolinol of Formula XXIII in asolvent such as DMF in the presence of a suitable base such as cesiumcarbonate. The reaction can be carried out at ambient temperature or atan elevated temperature, for example 65° C. or 85° C. Alternatively, thereaction can be carried out by treating a solution of a1H-imidazo[4,5-c]quinolinol of Formula XXIII in a solvent such as DMFwith sodium hydride and then adding a reagent of Formula Halide-Z—Y—R₄,Halide-Z—R₅, Halide-Z—Y—X—Y—R₄, or Halide-Z-Het. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Numerous reagents of Formulas Halide-Z—Y—R₄ and Halide-Z-Het arecommercially available, for example, bromo-substituted ketones, esters,and heterocycles. Other reagents of Formulas Halide-Z—Y—R₄, Halide-Z—R₅,Halide-Z—Y—X—Y—R₄, and Halide-Z-Het can be prepared using conventionalsynthetic methods; for example, a bromo-substituted acid halide ofFormula ClC(O)—Z—Br or BrC(O)—Z—Br can be treated with a secondary aminein a suitable solvent such as dichloromethane to provide a variety ofbromo-substituted amides of Formula Br—Z—C(O)—N(R₈)—R₄ or

wherein R₈, a, b, and A′ are as defined above. The reaction can be runat a sub-ambient temperature such as −25° C., and the product can beisolated using conventional methods.

Step (9) of Reaction Scheme I can alternatively be carried out bytreating a 1H-imidazo[4,5-c]quinolinol of Formula XXIII with an alcoholof Formula HO—Z—Y—R₄, HO—Z—R₅, or HO—Z-Het under Mitsunobu reactionconditions. Numerous alcohols of these formulas are commerciallyavailable, and others can be prepared using conventional syntheticmethods. The reaction is conveniently carried out by out by addingtriphenylphosphine and an alcohol of Formula HO—Z—Y—R₄, HO—Z-Het, orHO—Z—R₅, for example, 1-(2-hydroxyethyl)pyrrolidin-2-one or1-(3-hydroxypropyl)pyrrolidin-2-one, to a solution of a1H-imidazo[4,5-c]quinolinol of Formula XXIII in a suitable solvent suchas tetrahydrofuran and then slowly adding diisopropyl azodicarboxylateor diethyl azodicarboxylate. The reaction can be carried out at ambienttemperature or at a sub-ambient temperature, such as 0° C. The productcan be isolated using conventional methods.

In step (10) of Reaction Scheme I, an ether-substituted1H-imidazo[4,5-c]quinoline of Formula IX is oxidized to provide a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula X using a conventionaloxidizing agent capable of forming N-oxides. The reaction isconveniently carried out by adding 3-chloroperoxybenzoic acid to asolution of a compound of Formula IX in a solvent such asdichloromethane or chloroform. The reaction can be carried out atambient temperature, and the product can be isolated using conventionalmethods.

In step (11) of Reaction Scheme I, a 1H-imidazo[4,5-c]quinoline-5N-oxideof Formula X is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amineof Formula II. Step (11) can be carried out by the activation of anN-oxide of Formula X by conversion to an ester and then reacting theester with an aminating agent. Suitable activating agents include alkyl-or arylsulfonyl chlorides such as benzenesulfonyl chloride,methanesulfonyl chloride, or p-toluenesulfonyl chloride. Suitableaminating agents include ammonia, in the form of ammonium hydroxide, forexample, and ammonium salts such as ammonium carbonate, ammoniumbicarbonate, and ammonium phosphate. The reaction is convenientlycarried out by adding ammonium hydroxide to a solution of the N-oxide ofFormula X in a suitable solvent such as dichloromethane or chloroformand then adding p-toluenesulfonyl chloride. The reaction can be carriedout at ambient temperature. The product or pharmaceutically acceptablesalt thereof can be isolated using conventional methods.

Alternatively step (11) can be carried out by the reaction of a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula X with trichloroacetylisocyanate followed by base-promoted hydrolysis of the resultingintermediate to provide a 1H-imidazo[4,5-c]quinolin-4-amine of FormulaII. The reaction is conveniently carried out in two steps by (i) addingtrichloroacetyl isocyanate to a solution of the N-oxide of Formula X ina solvent such as dichloromethane and stirring at ambient temperature toprovide an isolable amide intermediate. In step (ii), a solution of theintermediate in methanol is treated with a base such as sodium methoxideor ammonium hydroxide at ambient temperature. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Steps (10) and (11) can alternatively be combined and carried out as aone-pot procedure by adding 3-chloroperoxybenzoic acid to a solution ofa compound of Formula IX in a solvent such as dichloromethane orchloroform and then adding ammonium hydroxide and p-toluenesulfonylchloride without isolating the N-oxide of Formula X. The product ofFormula II or pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

Compounds of the invention can also be prepared according to ReactionScheme II, where R, R₁, R₂, R₃, and n are as defined above. In ReactionScheme II, a benzyloxy-1H-imidazo[4,5-c]quinoline of Formula XXII isfirst oxidized to a benzyloxy-1H-imidazo[4,5-c]quinoline-5N-oxide ofFormula XXIV, which is then aminated in step (2) to provide abenzyloxy-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXV. In step (3)of Reaction Scheme II, the benzyl group of thebenzyloxy-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXV is cleaved toprovide a 1H-imidazo[4,5-c]quinolinol of Formula XXVI, which isconverted in step (4) to an ether-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula II. Steps (1), (2), (3),and (4) of Reaction Scheme II can be carried out as described for steps(10), (11), (8), and (9), respectively, of Reaction Scheme I.

For some embodiments, compounds shown in Reaction Scheme I can befurther elaborated using conventional synthetic methods. For example, anamine of Formula R₁—NH₂, used in step (5) of Reaction Scheme I, may besubstituted by a hydroxy or second amino group, which can be furtherfunctionalized before step (6) of Reaction Scheme I. For example, abenzyloxy-3-nitroquinolin-4-amine of Formula XX, in which R₁ has anamino substituent, can react with an acid chloride of Formula R₄C(O)Cl,a sulfonyl chloride of Formula R₄S(O)₂Cl, a sulfonic anhydride ofFormula (R₄S(O)₂)₂O, or an isocyanate of Formula R₄N═C═O to provide acompound of Formula XX in which R₁ is —X—Y—R₄, where X and R₄ are asdefined above, and Y is —N(R₈)-Q-, where R₈ is as defined above and Q is—C(O)—, —SO₂—, or —C(O)—NH—. Numerous acid chlorides, sulfonylchlorides, sulfonic anhydrides, and isocyanates are commerciallyavailable; others can be readily prepared using known synthetic methods.The reaction can be conveniently carried out by adding the sulfonicanhydride to a solution of a benzyloxy-3-nitroquinolin-4-amine ofFormula XX, in which R₁ has an amino substituent, and a base such astriethylamine in a suitable solvent such as dichloromethane. Thereaction can be carried out at ambient temperature. The product can thenbe treated according to steps (6) and (7) of Reaction Scheme I toprovide a benzyloxy-1H-imidazo[4,5-c]quinoline of Formula XXII, whichcan be treated as described in steps (8)-(11) of Reaction Scheme I orsteps (1)-(4) of Reaction Scheme II to provide a compound of Formula II.

Amines of Formula R₁—NH₂, used in step (5) of Reaction Scheme I, maycontain a protected functional group, such as atert-butoxycarbonyl-protected amino group or a isopropylideneketal-protected diol. The protecting group installed in step (5) may beremoved later in Reaction Scheme I or Reaction Scheme II to reveal, forexample, an amino substituent or a diol on the R₁ group. An amino groupintroduced in this manner may be functionalized as described above, ifdesired.

Functional groups can also be installed at R₁ using a variety of otherknown methods. See, for example, U.S. Pat. No. 4,689,338 (Gerster), U.S.Pat. No. 4,929,624 (Gerster et al.), U.S. Pat. No. 5,268,376 (Gerster),U.S. Pat. No. 5,389,640 (Gerster et al.), U.S. Pat. No. 6,331,539(Crooks et al.), U.S. Pat. No. 6,451,810 (Coleman et al.), U.S. Pat. No.6,541,485 (Crooks et al.), U.S. Pat. No. 6,660,747 (Crooks et al.), U.S.Pat. No. 6,670,372 (Charles et al.), U.S. Pat. No. 6,683,088 (Crooks etal.), U.S. Pat. No. 6,656,938 (Crooks et al.), U.S. Pat. No. 6,664,264(Dellaria et al.), U.S. Pat. No. 6,677,349 (Griesgraber), and U.S. Pat.No. 6,664,260 (Charles et al.).

Synthetic transformations can be made at R₂ if, for example, the acidchloride used in step (7) of Reaction Scheme I contains a protectedhydroxy or amino group. Several acid chlorides of this type, for exampleacetoxyacetyl chloride, are commercially available. Others can beprepared by known synthetic methods. In addition, a methoxyalkylenylgroup at R₂ is conveniently converted to a hydroxyalkylenyl group usingconventional methods. The demethylation can be carried out by treating acompound of Formula II wherein R₂ is a methoxyalkylenyl group with borontribromide in a suitable solvent such as dichloromethane at asub-ambient temperature such as 0° C. For other examples of syntheticelaborations of an R₂ group, see U.S. Pat. No. 5,389,640 (Gerster etal.).

Functional group transformations in an R₃ group are also possible usingknown synthetic methods. For example, a 1H-imidazo[4,5-c]quinoline ofFormula IX in which R₃ is —Z—C(O)OH and Z is as defined above, can beconverted to an amide of Formula IX in which R₃ is —Z—C(O)—N(R₈)—R₄,

wherein Z, R₁₀, R₈, R₄, a, b, and A are as defined above, using acoupling reagent. The reaction is conveniently carried out by treating asolution of the 1H-imidazo[4,5-c]quinoline of Formula IX, in which R₃ is—Z—C(O)OH, with a secondary amine and1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride. Thereaction can be carried out at ambient temperature in a suitable solventsuch as pyridine, and the product can be treated according to steps (10)and (11) of Reaction Scheme I to provide a compound of Formula II.

In another example, an R₃ group in a compound of Formula IX may containa —S-functional group, which can be oxidized to —S(O)₂— in step (10) ofReaction Scheme I using an excess of the oxidizing agent. Step (11) ofReaction Scheme I may then be carried out to provide a compound ofFormula II, wherein R₃ contains a —S(O)₂— functional group.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme III, where R, R₁, R₂, R₈, and n are definedas above; Z is selected from the group consisting of alkylene,alkenylene, and alkynylene wherein alkylene, alkenylene, and alkynylenecan be optionally interrupted with one or more —O— groups; and R_(3a) is

—Z—N(R₈)-Q-R₄ or —Z—R₅, wherein R₅ is

In step (1) of Reaction Scheme III, the amine of an amino alcohol ofFormula XXVII is protected with a tert-butoxy carbonyl (Boc) group toprovide a hydroxyalkylcarbamate of Formula XXVIII. Numerous aminoalcohols of Formula XXVII are commercially available; others can beprepared using known synthetic methods. The reaction is convenientlycarried out by treating the amino alcohol of Formula XXVII withdi-tert-butyl dicarbonate in the presence of a base such as aqueoussodium hydroxide. The reaction can be run at ambient temperature in asuitable solvent such as tetrahydrofuran, and the product can beisolated using conventional methods.

In step (2) of Reaction Scheme III, a hydroxyalkylcarbamate of FormulaXXVIII is converted to an iodoalkylcarbamate of Formula XXIX usingconventional methods. The reaction is conveniently carried out bytreating the hydroxyalkylcarbamate of Formula XXVIII with a solution ofiodine, triphenylphosphine, and imidazole. The reaction can be run atambient temperature in a suitable solvent such as dichloromethane, andthe product can be isolated using conventional methods.

In step (3) of Reaction Scheme III, a 1H-imidazo[4,5-c]quinolinol ofFormula XXIII is treated with an iodoalkylcarbamate of Formula XXIX toprovide an ether-substituted 1H-imidazo[4,5-c]quinoline of Formula XXX.The reaction can be carried out according to the Williamson conditionsdescribed in step (9) of Reaction Scheme I, and the product can beisolated using conventional methods.

In steps (4) and (5) of Reaction Scheme III, a1H-imidazo[4,5-c]quinoline of Formula XXX is oxidized to a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXXI, which is aminatedto provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXII, whichis a subgenus Formula VII. Steps (4) and (5) of Reaction Scheme III canbe carried out as described for steps (10) and (11), respectively, ofReaction Scheme I. In step (5), the preferred conditions for aminationare the activation of an N-oxide of Formula XXXI by conversion to anester and then reacting the ester with an aminating agent. Step (5) isconveniently carried out by adding ammonium hydroxide to a solution ofthe N-oxide of Formula XXXI in a suitable solvent such asdichloromethane and then adding p-toluenesulfonyl chloride and stirringat ambient temperature. The product or pharmaceutically acceptable saltthereof can be isolated using conventional methods.

In step (6) of Reaction Scheme III, the Boc protecting group of a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXII is removed to providean amino-substituted 1H-imidazo[4,5-c]quinolin-4-amine of FormulaXXXIII, which is a subgenus of Formula VIII. The reaction isconveniently carried out by adding a solution of hydrochloric acid inethanol to the 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXII. Thereaction can be carried out at an elevated temperature, for example, thereflux temperature of the solvent. The product or pharmaceuticallyacceptable salt thereof can be isolated by conventional methods.

In step (7) of Reaction Scheme III, an amino-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII is converted to a1H-imidazo[4,5-c]quinolin-1-yl compound of Formula IId, a subgenus ofFormulas I and II, using conventional methods. For example, anamino-substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIIIcan react with an acid chloride of Formula R₄C(O)Cl to provide acompound of Formula IId in which R_(3a) is —Z—N(R₈)—C(O)—R₄. Inaddition, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII canreact with sulfonyl chloride of Formula R₄S(O)₂Cl or a sulfonicanhydride of Formula (R₄S(O)₂)₂O to provide a compound of Formula IId inwhich R_(3a) is —Z—N(R₈)—S(O)₂—R₄. Numerous acid chlorides of FormulaR₄C(O)Cl, sulfonyl chlorides of Formula R₄S(O)₂Cl, and sulfonicanhydrides of Formula (R₄S(O)₂)₂O are commercially available; others canbe readily prepared using known synthetic methods. The reaction isconveniently carried out by adding the acid chloride of FormulaR₄C(O)Cl, sulfonyl chloride of Formula R₄S(O)₂Cl, or sulfonic anhydrideof Formula (R₄S(O)₂)₂O to a solution of the amino-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII in a suitablesolvent such as chloroform, dichloromethane, or1-methyl-2-pyrrolidinone. Optionally a base such as triethylamine can beadded. The reaction can be carried out at ambient temperature or asub-ambient temperature such as 0° C. The product or pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

Amides of Formula IId can alternatively be prepared by treating anamino-substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIIIwith a carboxylic acid of Formula R₄C(O)OH in the presence of a couplingreagent. The reaction is conveniently carried out by adding a solutionof a carboxylic acid of Formula R₄C(O)OH and a base such astriethylamine to a cooled solution of the amino-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.The reaction can be carried out in a suitable solvent such asdichloromethane at a sub-ambient temperature such as 0° C. The productor pharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Compounds of Formula IId where R_(3a) is —Z—R₅ and R₅ is

can be prepared by treating an amino-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII, wherein R₈ ishydrogen, with a chloroalkanesulfonyl chloride of Formula Cl—R₇S(O)₂Clor a chloroalkanoyl chloride of Formula Cl—R₇C(O)Cl. The reaction isconveniently carried out by adding the chloroalkanesulfonyl chloride orchloroalkanoyl chloride to a solution of the amino-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII in a suitablesolvent such as chloroform at ambient temperature. The isolableintermediate chloroalkanesulfonamide or chloroalkanamide can then betreated with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in asuitable solvent such as DMF to effect the cyclization. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Ureas of Formula IId, where R_(3a) is —Z—N(R₈)-Q-R₄, Q is—C(R₆)—N(R₈)—W—, R₆ is ═O, R₈ is as defined above, and W is a bond, canbe prepared by reacting an amino-substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII with isocyanates ofFormula R₄N═C═O. Numerous isocyanates of Formula R₄N═C═O arecommercially available; others can be readily prepared using knownsynthetic methods. The reaction can be conveniently carried out byadding the isocyanate of Formula R₄N═C═O to a solution of theamino-substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII ina suitable solvent such as dichloromethane or chloroform. Optionally abase such as triethylamine can be added. The reaction can be carried outat ambient temperature or a sub-ambient temperature such as 0° C.Alternatively, a compound of Formula XXXIII can be treated with anisocyanate of Formula R₄(CO)N═C═O, a thioisocyanate of Formula R₄N═C═S,a sulfonyl isocyanate of Formula R₄S(O)₂N═C═O, or a carbamoyl chlorideof Formula R₄N—(R₈)—C(O)Cl or

to provide a compound of Formula IId, where R_(3a) is —Z—N(R₈)-Q-R₄ or

wherein R₄, A, Z, a, and b are defined as above and Q is—C(R₆)—N(R₈)—W—, where R₆, R₈, and W are defined as above. The productor pharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Sulfamides of Formula IId, where R_(3a) is —Z—N(R₈)-Q-R₄, Q is—S(O)₂—N(R₈)—, and Z, R₄, and R₈ are as defined above, can be preparedby reacting a compound of Formula XXXIII with sulfuryl chloride togenerate a sulfamoyl chloride in situ, and then reacting the sulfamoylchloride with an amine of formula HN(R₈)R₄. Alternatively, sulfamides ofFormula IId can be prepared by reacting a compound of Formula XXXIIIwith a sulfamoyl chloride of formula R₄(R₈)N—S(O)₂Cl. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods. Many amines of Formula HN(R₈)R₄ and some sulfamoylchlorides of formula R₄(R₈)N—S(O)₂Cl are commercially available; otherscan be prepared using known synthetic methods. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Compounds of Formula IId, wherein R_(3a) is —Z—N(R₈)—R₄, and Z, R₄, andR₈ are as defined above, can be prepared by reductive alkylation of theamino-substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII,wherein R₈ is hydrogen. The alkylation is conveniently carried out intwo parts by (i) adding an aldehyde or ketone to a solution of aamino-substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII ora salt thereof in a suitable solvent such as DMF in the presence of abase such as N,N-diisopropylethylamine. In part (ii) the reduction iscarried out by adding a suitable reducing agent such as theborane-pyridine complex. Both part (i) and part (ii) can be carried outat ambient temperature, and the product or pharmaceutically acceptablesalt thereof can be isolated using conventional methods. In compounds ofFormula XXXIII, wherein R₈ is hydrogen, it is convenient to carry outthe reductive alkylation followed by reaction with an acid chloride,sulfonyl chloride, sulfonic anhydride, isocyanate, or carbamoyl chlorideas described above to provide a compound of Formula IId, wherein R_(3a)is —Z—N(R₈)-Q-R₄, wherein Z, R₄, R₈, and Q are as defined above.

Compounds of the invention can be prepared according to Reaction SchemeIV, where R, R₁, R₂, R₁₀, and n are as defined above; Z_(a) is selectedfrom the group consisting of a bond, alkylene, alkenylene, andalkynylene wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups; R_(3b) is

wherein R₄, R₆, A, Q, a, and b are as defined above. Steps (1) through(7) of Reaction Scheme IV can be run as described in steps (1) through(7) of Reaction Scheme III to provide compounds of Formula IIe, asubgenus of Formulas I and II.

Alternatively, a compound of Formula XXXV can react with a1H-imidazo[4,5-c]quinolinol of Formula XXIII under the Mitsunobureaction conditions described in step (9) of Reaction Scheme I. Forexample, combining a 1H-imidazo[4,5-c]quinolinol of Formula XXIII,triphenylphosphine, and tert-butyl 4-hydroxy-1-piperdinecarboxylate inTHF at 5° C. or ambient temperature and slowly adding diisopropylazodicarboxylate provides a compound of Formula XXXVII wherein Z_(a) isa bond and R₁₀ is pentylene.

The oxidation in step (4) of Reaction Scheme IV can be carried outaccording to the reaction conditions described in step (10) of ReactionScheme I or by heating a solution of a compound of Formula XXXVII in asuitable solvent such as ethyl acetate with peracetic acid at atemperature such as 50° C. and then adding sodium metabisulfate. Theproduct can be isolated using conventional methods. Steps (5) through(7) of Reaction Scheme IV can then be used to provide a compound ofFormula IIe.

Compounds of the invention can also be prepared according to ReactionScheme V, wherein R, R₁, R₂, and n are as defined above; Z is selectedfrom the group consisting of alkylene, alkenylene, and alkynylenewherein alkylene, alkenylene, and alkynylene can be optionallyinterrupted with one or more —O— groups; and R_(3c) is —Z-Het,—Z-Het′-R₄, or —Z-Het′-Y—R₄, wherein Het or Het′ is attached to Z at anitrogen atom.

In step (1) of Reaction Scheme V, a 1H-imidazo[4,5-c]quinolinol ofFormula XXVI is treated with a dihalide of Formula I—Z—Cl or Br—Z—Clusing the Williamson conditions described in step (9) of Reaction SchemeI to provide a chloro-substituted compound of Formula XLI, a subgenus ofFormulas I and II. The product or pharmaceutically acceptable saltthereof can be isolated using conventional methods.

In step (2) of Reaction Scheme V, a chloro-substituted compound ofFormula XLI is treated with a cyclic secondary amine to provide acompound of Formula IIf, a subgenus of Formulas I and II. Many cyclicsecondary amines are commercially available, such as unsubstituted orsubstituted aziridines, pyrrolidines, piperidines, morpholines,thiazolidines, thiomorpholines, piperazines, azepanes, diazepanes,dihydroisoquinolines, octahydroisoquinolines, dihydroquinolines,octahydroquinolines, and dihydroimidazoles; others can be prepared usingconventional methods. The reaction is conveniently carried out by addinga cyclic secondary amine to a compound of Formula XLI in a suitablesolvent such as DMF. The reaction is conveniently carried out in thepresence of a base such as potassium carbonate at an elevatedtemperature such as 65° C. The product of Formula IIf or apharmaceutically acceptable salt thereof can be isolated by conventionalmethods.

Compounds of Formula IIf are also prepared from1H-imidazo[4,5-c]quinolinols of Formula XXIII, shown in Reaction SchemeI. A 1H-imidazo[4,5-c]quinolinol of Formula XXIII is first treated witha dihalide of Formula I—Z—Cl or Br—Z—Cl according to step (1) ofReaction Scheme V. The product is then oxidized and aminated accordingto the methods described in steps (10) and (11) of Reaction Scheme I toprovide a compound of Formula XLI, which is then treated with a cyclicsecondary amine as described in step (2) of Reaction Scheme V to providea compound of Formula IIf. The product or pharmaceutically acceptablesalt thereof can be isolated by conventional methods.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound or salt of the invention as describedabove in combination with a pharmaceutically acceptable carrier.

The terms “a therapeutically effective amount” and “effective amount”mean an amount of the compound or salt sufficient to induce atherapeutic or prophylactic effect, such as cytokine induction,immunomodulation, antitumor activity, and/or antiviral activity.Although the exact amount of active compound or salt used in apharmaceutical composition of the invention will vary according tofactors known to those of skill in the art, such as the physical andchemical nature of the compound or salt, the nature of the carrier, andthe intended dosing regimen, it is anticipated that the compositions ofthe invention will contain sufficient active ingredient to provide adose of about 100 nanograms per kilogram (ng/kg) to about 50 milligramsper kilogram (mg/kg), preferably about 10 micrograms per kilogram(μg/kg) to about 5 mg/kg, of the compound or salt to the subject. Avariety of dosage forms may be used, such as tablets, lozenges,capsules, parenteral formulations, syrups, creams, ointments, aerosolformulations, transdermal patches, transmucosal patches and the like.

The compounds or salts of the invention can be administered as thesingle therapeutic agent in the treatment regimen, or the compounds orsalts of the invention may be administered in combination with oneanother or with other active agents, including additional immuneresponse modifiers, antivirals, antibiotics, antibodies, proteins,peptides, oligonucleotides, etc.

Compounds or salts of the invention have been shown to induce or inhibitthe production of certain cytokines in experiments performed accordingto the tests set forth below. These results indicate that the compoundsor salts are useful as immune response modifiers that can modulate theimmune response in a number of different ways, rendering them useful inthe treatment of a variety of disorders.

Cytokines whose production may be induced by the administration ofcompounds or salts of the invention generally include interferon-α(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds or salts of the invention include IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12, and a variety of other cytokines. Among other effects,these and other cytokines can inhibit virus production and tumor cellgrowth, making the compounds or salts useful in the treatment of viraldiseases and neoplastic diseases. Accordingly, the invention provides amethod of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound or salt or compositionof the invention to the animal. The animal to which the compound or saltor composition is administered for induction of cytokine biosynthesismay have a disease as described infra, for example a viral disease or aneoplastic disease, and administration of the compound or salt mayprovide therapeutic treatment. Alternatively, the compound or salt maybe administered to the animal prior to the animal acquiring the diseaseso that administration of the compound or salt may provide aprophylactic treatment.

In addition to the ability to induce the production of cytokines,compounds or salts of the invention can affect other aspects of theinnate immune response. For example, natural killer cell activity may bestimulated, an effect that may be due to cytokine induction. Thecompounds or salts may also activate macrophages, which in turnstimulate secretion of nitric oxide and the production of additionalcytokines. Further, the compounds or salts may cause proliferation anddifferentiation of B-lymphocytes.

Compounds or salts of the invention can also have an effect on theacquired immune response. For example, the production of the T helpertype 1 (T_(H)1) cytokine IFN-γ may be induced indirectly and theproduction of the T helper type 2 (T_(H)2) cytokines IL-4, IL-5, andIL-13 may be inhibited upon administration of the compounds or salts.

Other cytokines whose production may be inhibited by the administrationof compounds or salts of the invention include tumor necrosis factor-α(TNF-α). Among other effects, inhibition of TNF-α production can provideprophylaxis or therapeutic treatment of TNF-α mediated diseases inanimals, making the compounds or salt useful in the treatment of, forexample, autoimmune diseases. Accordingly, the invention provides amethod of inhibiting TNF-α biosynthesis in an animal comprisingadministering an effective amount of a compound or salt or compositionof the invention to the animal. The animal to which the compound or saltor composition is administered for inhibition of TNF-α biosynthesis mayhave a disease as described infra, for example an autoimmune disease,and administration of the compound or salt may provide therapeutictreatment. Alternatively, the compound or salt may be administered tothe animal prior to the animal acquiring the disease so thatadministration of the compound or salt may provide a prophylactictreatment.

Whether for prophylaxis or therapeutic treatment of a disease, andwhether for effecting innate or acquired immunity, the compound or saltor composition may be administered alone or in combination with one ormore active components as in, for example, a vaccine adjuvant. Whenadministered with other components, the compound or salt and othercomponent or components may be administered separately; together butindependently such as in a solution; or together and associated with oneanother such as (a) covalently linked or (b) non-covalently associated,e.g., in a colloidal suspension.

Conditions for which IRMs identified herein may be used as treatmentsinclude, but are not limited to:

(a) viral diseases such as, for example, diseases resulting frominfection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, orVZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, ormolluscum contagiosum), a picornavirus (e.g., rhinovirus orenterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus(e.g., parainfluenzavirus, mumps virus, measles virus, and respiratorysyncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g.,papillomaviruses, such as those that cause genital warts, common warts,or plantar warts), a hepadnavirus (e.g., hepatitis B virus), aflavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus(e.g., a lentivirus such as HIV);

(b) bacterial diseases such as, for example, diseases resulting frominfection by bacteria of, for example, the genus Escherichia,Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria,Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria,Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter,Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia,Haemophilus, or Bordetella;

(c) other infectious diseases, such chlamydia, fungal diseases includingbut not limited to candidiasis, aspergillosis, histoplasmosis,cryptococcal meningitis, or parasitic diseases including but not limitedto malaria, pneumocystis carnii pneumonia, leishmaniasis,cryptosporidiosis, toxoplasmosis, and trypanosome infection;

(d) neoplastic diseases, such as intraepithelial neoplasias, cervicaldysplasia, actinic keratosis, basal cell carcinoma, squamous cellcarcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemiasincluding but not limited to myelogeous leukemia, chronic lymphocyticleukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;

(e) T_(H)2-mediated, atopic diseases, such as atopic dermatitis oreczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen'ssyndrome;

(f) certain autoimmune diseases such as systemic lupus erythematosus,essential thrombocythaemia, multiple sclerosis, discoid lupus, alopeciaareata; and

(g) diseases associated with wound repair such as, for example,inhibition of keloid formation and other types of scarring (e.g.,enhancing wound healing, including chronic wounds).

Additionally, an IRM compound or salt of the present invention may beuseful as a vaccine adjuvant for use in conjunction with any materialthat raises either humoral and/or cell mediated immune response, suchas, for example, live viral, bacterial, or parasitic immunogens;inactivated viral, tumor-derived, protozoal, organism-derived, fungal,or bacterial immunogens, toxoids, toxins; self-antigens;polysaccharides; proteins; glycoproteins; peptides; cellular vaccines;DNA vaccines; autologous vaccines; recombinant proteins; and the like,for use in connection with, for example, BCG, cholera, plague, typhoid,hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B,parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever,tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningococcaland pneumococcal vaccines, adenovirus, HIV, chicken pox,cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2,hog cholera, Japanese encephalitis, respiratory syncytial virus,rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.

Certain IRM compounds or salts of the present invention may beparticularly helpful in individuals having compromised immune function.For example, certain compounds or salts may be used for treating theopportunistic infections and tumors that occur after suppression of cellmediated immunity in, for example, transplant patients, cancer patientsand HIV patients.

Thus, one or more of the above diseases or types of diseases, forexample, a viral disease or a neoplastic disease may be treated in ananimal in need thereof (having the disease) by administering atherapeutically effective amount of a compound or salt of the inventionto the animal.

An amount of a compound or salt effective to induce or inhibit cytokinebiosynthesis is an amount sufficient to cause one or more cell types,such as monocytes, macrophages, dendritic cells and B-cells to producean amount of one or more cytokines such as, for example, IFN-α, TNF-α,IL-1, IL-6, IL-10 and IL-12 that is increased (induced) or decreased(inhibited) over a background level of such cytokines. The preciseamount will vary according to factors known in the art but is expectedto be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10μg/kg to about 5 mg/kg. The invention also provides a method of treatinga viral infection in an animal and a method of treating a neoplasticdisease in an animal comprising administering an effective amount of acompound or salt or composition of the invention to the animal. Anamount effective to treat or inhibit a viral infection is an amount thatwill cause a reduction in one or more of the manifestations of viralinfection, such as viral lesions, viral load, rate of virus production,and mortality as compared to untreated control animals. The preciseamount that is effective for such treatment will vary according tofactors known in the art but is expected to be a dose of about 100 ng/kgto about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amountof a compound or salt effective to treat a neoplastic condition is anamount that will cause a reduction in tumor size or in the number oftumor foci. Again, the precise amount will vary according to factorsknown in the art but is expected to be a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

EXAMPLES Example 12-(4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)-1-phenylethanone

Part A

A mixture of triethyl orthoformate (92 mL, 0.55 mol) and2,2-dimethyl-[1,3]-dioxane-4,6-dione (75.3 g, 0.522 mol) (Meldrum'sacid) was heated at 55° C. for 90 minutes and then cooled to 45° C. Asolution of 3-benzyloxyaniline (100.2 g, 0.5029 mol) in methanol (200mL) was slowly added to the reaction over a period 45 minutes whilemaintaining the reaction temperature below 50° C. The reaction was thenheated at 45° C. for one hour, allowed to cool to room temperature, andstirred overnight. The reaction mixture was cooled to 1° C., and theproduct was isolated by filtration and washed with cold ethanol (˜400mL) until the filtrate was colorless.5-{[(3-Benzyloxy)phenylimino]methyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione(170.65 g) was isolated as a tan, powdery solid.

¹H NMR (300 MHz, DMSO-d₆) δ 11.21 (d, J=14.2 Hz, 1H), 8.61 (d, J=14.2Hz, 1H), 7.49-7.30 (m, 7H), 7.12 (dd, J=8.1, 1.96 Hz, 1H), 6.91 (dd,J=8.4, 2.1 Hz, 1H), 5.16 (s, 2H), 1.68 (s, 6H).

Part B

A mixture of5-{[(3-benzyloxy)phenylimino]methyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione(170.65 g, 0.483 mol) and DOWTHERM A heat transfer fluid (800 mL) washeated to 100° C. and then slowly added to a flask containing DOWTHERM Aheat transfer fluid (1.3 L, heated at 210° C.) over a period of 40minutes. During the addition, the reaction temperature was not allowedto fall below 207° C. Following the addition, the reaction was stirredat 210° C. for one hour, and then allowed to cool to ambienttemperature. A precipitate formed, which was isolated by filtration,washed with diethyl ether (1.7 L) and acetone (0.5 L), and dried in anoven to provide 76.5 g of 7-benzyloxyquinolin-4-ol as a tan powder.

¹H NMR (300 MHz, DMSO-d₆) δ 11.53 (s, 1H), 7.99 (dd, J=7.4, 2.4 Hz, 1H),7.79 (d, J=7.4 Hz, 1H), 7.50-7.32 (m, 5H), 7.00 (s, 1H), 6.98 (dd,J=7.4, 2.5 Hz, 1H), 5.93 (d, J=7.5 Hz, 1H), 5.20 (s, 2H).

Part C

A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol) andpropionic acid (700 mL) was heated to 125° C. with vigorous stirring.Nitric acid (23.11 mL of 16 M) was slowly added over a period of 30minutes while maintaining the reaction temperature between 121° C. and125° C. After the addition, the reaction was stirred at 125° C. for 1hour then allowed to cool to ambient temperature. The resulting solidwas isolated by filtration, washed with water, and dried in an oven for1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinolin-4-ol as agrayish powder.

¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 9.12 (s, 1H), 8.17 (dd,J=6.3, 3.3 Hz, 1H), 7.51-7.33 (m, 5H), 7.21-7.17 (m, 2H), 5.25 (s, 2H).

Part D

N,N-Dimethylformamide (100 mL) (DMF) was cooled to 0° C., andphosphorous oxychloride (27.5 mL, 0.295 mol) was added dropwise. Theresulting solution was stirred for 25 minutes and then added dropwise toa mixture of 7-benzyloxy-3-nitroquinolin-4-ol (72.87 g, 0.2459 mol) inDMF (400 mL). Following the addition, the reaction was heated at 100° C.for 5 minutes, cooled to ambient temperature, and poured into ice waterwith stirring. A tan precipitate formed, which was isolated byfiltration and dissolved in dichloromethane. The resulting solution wasdried over magnesium sulfate, filtered, and concentrated under reducedpressure to yield 72.9 g of 7-benzyloxy-4-chloro-3-nitroquinoline as alight brown solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.36 (d, J=8.7 Hz, 1H), 7.71(d, J=2.4 Hz, 1H), 7.66 (dd, J=9.3, 2.4 Hz, 1H), 7.56-7.51 (m, 2H),7.46-7.34 (m, 3H), 5.40 (s, 2H).

Part E

Triethylamine (38.6 mL, 0.277 mol) was added to a solution of7-benzyloxy-4-chloro-3-nitroquinoline (72.9 g, 0.232 mol) indichloromethane (1200 mL). Isobutylamine (25.24 mL, 0.2540 mol) was thenadded, and the reaction mixture was stirred for 18 hours at ambienttemperature. The reaction mixture was diluted with dichloromethane,washed sequentially with water (2×) and brine, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toyield 67.4 g of (7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amineas a brown solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (t, J=4.8 Hz, 1H), 9.07 (s, 1H), 8.42(d, J=9.4 Hz, 1H), 7.53-7.49 (m, 2H), 7.45-7.32 (m, 4H), 7.27 (dd,J=9.3, 2.6 Hz, 1H), 5.32 (s, 2H), 3.60 (t, J=6.0 Hz, 2H), 2.00 (septet,J=6.7 Hz, 1H), 0.96 (d, J=6.3 Hz, 6H).

Part F

Sodium borohydride (29.0 g, 0.767 mol) was added in small portions to asolution of nickel(II)chloride (22.8 g, 0.096 mol) in methanol (1.25 L).A solution of (7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amine(67.4 g, 0.192 mol) in methanol (300 mL) and dichloromethane (300 mL)was added to the resulting mixture. A precipitate was present and wasdissolved by the addition of dichloromethane (500 mL). Additional sodiumborohydride (˜10 g) was added in small portions until the(7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amine was consumed.The reaction mixture was filtered through a layer of CELITE filter aid,and the filter cake was washed with 50:50 dichloromethane:methanol. Thefiltrate was concentrated under reduced pressure, and the black, oilyresidue was treated with water and dichloromethane. The organic solutionwas washed with water and brine, dried over magnesium sulfate, andfiltered. The filtrate was treated with activated charcoal, filtered,and concentrated under reduced pressure to yield 55.4 g of7-benzyloxy-N⁴-(2-methylpropyl)quinoline-3,4-diamine a brown semi-solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.94 (d, J=9.4 Hz, 1H),7.51-7.48 (m, 2H), 7.43-7.30 (m, 3H), 7.21 (d, J=3.2 Hz, 1H), 7.10 (dd,J=9.5, 2.4 Hz, 1H), 5.18 (s, 2H), 4.92 (t, J=7.0 Hz, 1H), 4.70 (s, 2H),3.04 (t, J=6.9 Hz, 2H), 1.75 (septet, J=6.8 Hz, 1H), 0.89 (d, J=6.3 Hz,6H).

Part G

Trimethyl orthobutyrate (29.75 mL, 0.1859 mol) was added in threeportions to a solution of7-benzyloxy-N⁴-(2-methylpropyl)quinoline-3,4-diamine (54.6 g, 0.170 mol)in toluene (795 mL). Pyridine hydrochloride (1.96 g) was then added, andthe reaction was heated at 105° C. and stirred for four hours.Additional trimethyl orthobutyrate (7 mL, 40 mmol) was then added, andthe reaction was stirred for three hours. The reaction was allowed tocool to ambient temperature, and the solvent was removed under reducedpressure. The oily residue was treated with chloroform, which wasremoved under reduced pressure to remove residual toluene, and thenagain diluted with chloroform (1.2 L). The resulting solution was washedsequentially with 5% aqueous sodium bicarbonate, water, and brine; driedover magnesium sulfate; filtered; and concentrated under reducedpressure to yield 60.3 g of7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as anoily brown solid, containing a small amount of toluene (0.93equivalents).

¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.68(d, J=2.6 Hz, 1H), 7.53-7.12 (m, 6H), 5.31 (s, 2H), 4.42 (d, J=7.5 Hz,2H), 2.94 (t, J=7.5 Hz, 2H), 2.25-2.09 (m, 1H), 1.90 (sextet, J=7.4 Hz,2H), 1.04 (t, J=7.5 Hz, 3H), 0.89 (d, J=6.3 Hz, 6H).

Part H

3-Chloroperoxybenzoic acid (60% pure, 22.9 g, 79.6 mmol) (mCPBA) wasadded in portions to a solution of7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (27.0g, 72.3 mmol) in dichloromethane (1 L), and the reaction was stirred for30 minutes. Water (1 L) was added, and the resulting mixture was stirredfor 30 minutes. The organic layer was washed with 1% aqueous sodiumcarbonate (2×200 mL), dried over magnesium sulfate, filtered, andconcentrated under reduced pressure.

Part I

The material from Part H was dissolved in dichloromethane (800 mL), andconcentrated ammonium hydroxide (300 mL) was added. p-Toluenesulfonylchloride (16.6 g, 86.8 mmol) was added in small portions to theresulting mixture, and the reaction was stirred for 30 minutes and thendiluted with water. The organic layer was dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The crude product wasrecrystallized from acetonitrile to provide 21.4 g of7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amineas feathery, off-white crystals, mp 206.2-208.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=9.1 Hz, 1H), 7.52-7.28 (m, 5H),7.12 (d, J=2.4 Hz, 1H), 6.97 (dd, J=8.9, 2.8 Hz, 1H), 6.38 (s, 2H), 5.20(s, 2H), 4.28 (d, J=6.8 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.21-2.08 (m,1H), 1.83 (sextet, J=7.3 Hz, 2H), 1.01 (t, J=7.5 Hz, 3H), 0.91 (d, J=7.0Hz, 6H).

Part J

7-Benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(21.4 g, 55.1 mmol) was dissolved in refluxing ethanol (2 L), and 10%palladium on carbon (5.4 g, 5.1 mmol) was added to the warm solution.The reaction was placed under hydrogen pressure (50 psi, 3.4×10⁵ Pa)overnight. The catalyst was removed by filtration and washed with hotethanol (500 mL) and methanol (400 mL). The filtrate was concentratedunder reduced pressure to yield 14.5 g of an off-white solid. A smallportion of the solid was recrystallized from 2-propanol to provide4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol aswhite crystals, mp>265° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 7.78 (d, J=8.9 Hz, 1H),6.95 (d, J=2.5 Hz, 1H), 6.79 (dd, J=8.9, 2.6 Hz, 1H), 6.29 (br s, 2H),4.26 (d, J=7.4 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.14 (septet, J=6.7 Hz,1H), 1.88-1.77 (m, 2H), 1.01 (t, J=7.3 Hz, 3H), 0.91 (d, J=6.6 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ □□156.1, 152.3, 151.9, 146.9, 133.1, 126.5,121.2, 111.9, 109.9, 108.4, 51.3, 28.8, 28.7, 21.0, 19.3, 13.9;

MS (APCI) m/z 299 (M+H)⁺;

Anal. Calcd. for C₁₇H₂₂N₄O: % C, 68.43; % H, 7.43; % N, 18.78. Found: %C, 68.38; % H, 7.27; % N, 18.74.

Part K

A warm solution of4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (266mg, 0.891 mmol) in DMF (20 mL) was cooled to approximately 0° C. Solidcesium carbonate (580 mg, 1.78 mmol) was added. After ten minutes,2-bromoacetophenone (186 mg, 0.935 mmol) was added in one portion, andthe reaction was allowed to warm to room temperature and was stirredovernight. An analysis by high-performance liquid chromatography (HPLC)indicated the presence of starting material. Additional2-bromoacetophenone was added, and the reaction was stirred for sixhours. The reaction was poured into deionized water (200-300 mL) andstirred for 15 hours. The resulting precipitate was isolated byfiltration and purified by column chromatography on silica gel (elutingwith chloroform:methanol ranging in ratios from 99.5:0.5 to 98:2). Theproduct was then recrystallized from acetonitrile, isolated byfiltration, and dried overnight under high vacuum to provide 222 mg of2-(4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)-1-phenylethanoneas white crystals, mp 178.0-180.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.04-8.00 (m, 2H), 7.81 (d, J=9.1 Hz, 1H),7.65-7.59 (m, 1H), 7.54-7.48 (m, 2H), 7.23 (d, J=2.7 Hz, 1H), 7.12 (dd,J=9.0, 2.7 Hz, 1H), 5.42 (s, 2H), 5.36 (br s, 2H), 4.20 (d, J=7.5 Hz,2H), 2.86 (t, J=7.9 Hz, 2H), 2.34 (septet, J=6.8 Hz, 1H), 1.97-1.87 (m,2H), 1.08 (t, J=7.4 Hz, 3H), 1.00 (d, J=6.7 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 193.7, 156.9, 153.1, 151.4, 146.3, 134.5,133.8, 133.7, 128.8, 127.9, 125.7, 121.0, 113.4, 110.4, 108.5, 70.4,52.4, 29.6, 29.0, 21.4, 19.7, 14.0;

MS (APCI) m/z 417 (M+H)⁺;

Anal. Calcd. for C₂₅H₂₈N₄O₂: % C, 72.09; % H, 6.78; % N, 13.45. Found: %C, 71.89; % H, 6.58; % N, 13.24.

Example 28-(2-Aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

The general procedure described in Part A of Example 1 was used with thefollowing modification. A solution of 4-benzyloxyaniline (100 g, 0.5mol) in methanol (150 mL) was used in lieu of a solution of3-benzyloxyaniline. The addition of this solution was carried out over aperiod of one hour while maintaining the temperature between 57-60° C.The reaction product,5-{[(4-benzyloxy)phenylimino)]methyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione(136.7 g) was isolated as a yellow powder.

¹H NMR (300 MHz, DMSO-d₆) δ 11.23 (d, J=15.2 Hz, 1H), 8.46 (d, J=14.3Hz, 1H), 7.53-7.30 (m, 7H), 7.10-7.04 (m, 2H), 5.13 (s, 2H), 1.66 (s,6H).

Part B

A solution of5-{[(4-benzyloxy)phenylimino)]methyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione(127.2 g, 0.360 mol) and DOWTHERM A heat transfer fluid (500 mL) washeated to 100° C. and then slowly added to a flask containing DOWTHERM Aheat transfer fluid (1 L, heated at 250° C.) over a period of 90minutes. During the addition, the reaction temperature was not allowedto fall below 245° C. Following the addition, the reaction was stirredat 250° C. for 30 minutes, and then allowed to cool to ambienttemperature. A precipitate formed, which was isolated by filtration,washed with diethyl ether (1 L) and acetone (250 mL), and dried for twohours under vacuum in to provide 65.7 g of 6-benzyloxyquinolin-4-ol as ayellow powder.

¹H NMR (300 MHz, DMSO-d₆) δ 11.72 (s, 1H), 7.84 (d, J=7.3 Hz, 1H), 7.59(m, 8H), 5.98 (d, J=7.0 Hz, 1H), 5.18 (s, 2H).

Part C

The general method described in Part C of Example 1 was followed using6-benzyloxyquinolin-4-ol (65.7 g, 0.261 mol) in lieu of7-benzyloxyquinolin-4-ol. The reaction precipitate was isolated byfiltration; washed with propionic acid (600 mL), isopropanol (500 mL)and diethyl ether (500 mL); and dried for two days under vacuum toprovide 46.01 g of 6-benzyloxy-3-nitroquinolin-4-ol as a tan powder,containing 5% 6-benzyloxyquinolin-4-ol.

¹H NMR (300 MHz, DMSO-d₆) δ 12.98 (s, 1H), 9.12 (s, 1H), 7.75 (d, J=3.3Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.53-7.30 (m, 6H), 5.25 (s, 2H).

Part D

The general method described in Part D of Example 1 was used to convert6-benzyloxy-3-nitroquinolin-4-ol (46.93 g, 158.4 mmol) to6-benzyloxy-4-chloro-3-nitroquinoline, which was isolated as a tan solidcontaining some DMF.

¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.16 (d, J=9.1 Hz, 1H), 7.80(dd, J=9.1, 2.8 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.57-7.53 (m, 2H),7.45-7.34 (m, 3H), 5.39 (s, 2H).

Part E

Triethylamine (44 mL, 0.32 mol) was added to a solution of the materialfrom Part D in dichloromethane (790 mL). n-Propylamine (19.48 mL, 237.0mmol) was then added over a period of 25 minutes, and the reaction wasstirred for 18 hours. The reaction mixture was diluted withdichloromethane (500 mL), washed sequentially with water and brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The crude product was recrystallized from 2-propanol toprovide 39.1 g of (6-benzyloxy-3-nitroquinolin-4-yl)propylamine as fine,yellowish-brown needles.

¹H NMR (300 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.57 (s, 1H), 7.93 (d, J=3.1Hz, 1H), 7.85 (d, J=9.5 Hz, 1H), 7.58-7.33 (m, 6H), 5.30 (s, 2H),3.41-3.35 (m, 2H), 1.67 (sextet, J=7.3 Hz, 2H), 0.87 (t, J=7.5 Hz, 3H).

Part F

(6-Benzyloxy-3-nitroquinolin-4-yl)propylamine (18.00 g, 53.35 mmol), 5%platinum on carbon (5.3 g), toluene (200 mL) and 2-propanol (20 mL) wereadded to a Parr vessel. The vessel was purged with nitrogen and thenplaced under hydrogen pressure (30 psi, 2.1×10⁵ Pa) and shaken for 20minutes. The reaction mixture was filtered through a layer of CELITEfilter aid, and the filter cake was washed with toluene (1 L) and2-propanol (1 L). The orange filtrate was concentrated under reducedpressure. Heptane was added to the residue and subsequently removedunder reduced pressure. The residue was dried under vacuum (0.1 torr,13.3 Pa) for 30 minutes to provide 17.0 g of6-benzyloxy-N⁴-propylquinoline-3,4-diamine as a viscous, brown oilcontaining some toluene.

¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.52(d, J=1.9 Hz, 1H), 7.43-7.11 (m, 5H), 7.05 (dd, J=9.4, 2.5 Hz, 1H), 5.22(s, 2H), 4.99 (s, 2H), 4.62 (t, J=6.7 Hz, 1H), 2.99 (q, J=7.1 Hz, 2H),1.47 (sextet, J=7.3 Hz, 2H), 0.85 (t, J=7.2 Hz, 3H).

Part G

A solution of ethoxyacetyl chloride (6.53 g, 53.3 mmol) indichloromethane (65 mL) was added dropwise to a solution of the materialfrom Part F in dichloromethane (200 mL), and the reaction was stirredfor 16 hours. A precipitate formed and was isolated by filtration andwashed with cold hexanes. The solid was dried for 30 minutes underreduced pressure to provide 16.1 g ofN-(6-benzyloxy-4-propylaminoquinolin-3-yl)-2-ethoxyacetamidehydrochloride as a tan powder.

¹H NMR (300 MHz, DMSO-d₆) δ 14.14 (s, 1H), 9.74 (s, 1H), 8.56 (s, 1H),8.43 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.68 (dd,J=9.4, 2.6 Hz, 1H), 7.56-7.35 (m, 5H), 5.30 (s, 2H), 4.11 (s, 2H), 3.64(q, J=7.1 Hz, 2H), 3.68-3.60 (m, 2H), 1.61 (sextet, J=7.4 Hz, 2H), 1.23(t, J=7.2 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H).

Part H

Triethylamine (22.16 mL, 159.0 mmol) was added to a solution ofN-(6-benzyloxy-4-propylaminoquinolin-3-yl)-2-ethoxyacetamidehydrochloride (16.1 g) in ethanol (265 mL), and the reaction mixture washeated at reflux and stirred for 3 hours. The reaction mixture wasallowed to cool to ambient temperature. The ethanol was removed underreduced pressure and the residue dissolved in chloroform. The resultingsolution was washed sequentially with water and brine, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting oil was dissolved in acetonitrile and concentrated underreduced pressure to yield 14.32 g of8-benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline as abrown, crystalline solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.64(d, J=2.6 Hz, 1H), 7.54-7.33 (m, 6H), 5.38 (s, 2H), 4.83 (s, 2H), 4.59(at, J=7.8 Hz, 2H), 3.57 (q, J=7.0 Hz, 2H), 1.84 (sextet, J=7.5 Hz, 2H),1.16 (t, J=7.3 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H).

Part I

8-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline (15.00 g,39.84 mmol) and ethanol (300 mL) were added to a Parr vessel. A mixtureof palladium hydroxide (2.0 g, 20% on carbon) in ethanol (100 mL) wasthen added. The vessel was purged with nitrogen, placed under hydrogenpressure (25 psi, 1.7×10⁵), and shaken for three hours. The vessel wasthen refilled with hydrogen (25 psi, 1.7×10⁵) and shaken for 18 hours.The reaction mixture was filtered through a layer of CELITE filter aid,and the filter cake was washed with methanol (2 L). The filtrate wasconcentrated under reduced pressure, and the resulting orange oil wasdissolved in toluene and concentrated under reduced pressure to provide10.7 g of 2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol as agranular, orange solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.94 (s, 1H), 7.99 (d, J=8.7Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.24 (dd, J=8.8, 2.5 Hz, 1H), 4.82 (s,2H), 4.51 (at, J=7.7 Hz, 2H), 3.57 (q, J=7.0 Hz, 2H), 1.91 (sextet,J=7.7 Hz, 2H), 1.16 (t, J=6.7 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H).

Part J

A solution of di-tert-butyl dicarbonate (36.0 g, 0.165 mol) intetrahydrofuran (THF) (80 mL) was added dropwise to a solution of2-aminoethanol (10.0 g, 0.164 mol) in THF (50 mL) and 10% aqueous sodiumhydroxide (66 mL), and the reaction was stirred for 16 hours. Aprecipitate formed. The THF was removed under reduced pressure, and 15%aqueous potassium hydrogen sulfate was slowly added to adjust theresulting mixture to pH 3. The mixture was then extracted with ethylacetate (3×), and the combined extracts were washed sequentially withwater and brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to afford 23.6 g of tert-butyl2-hydroxyethylcarbamate as a colorless oil containing some ethylacetate.

Part K

Iodine (30.46 g, 0.120 mol) was added in three portions to a solution oftriphenylphosphine (28.85 g, 0.110 mol) and imidazole (7.49 g, 0.110mol) in dichloromethane (654 mL), and the reaction was stirred until theiodine dissolved. A solution of tert-butyl 2-hydroxyethylcarbamate (17.7g, 0.110 mol) in dichloromethane (150 mL) was added over a period of 45minutes, and the reaction was stirred for 16 hours at ambienttemperature. The reaction mixture was poured into saturated aqueoussodium thiosulfate and stirred until the solution became colorless. Theorganic layer was washed sequentially with saturated aqueous sodiumthiosulfate, water, and brine; dried over magnesium sulfate; filtered;and concentrated under reduced pressure. The resulting pale yellow oilwas purified by column chromatography on silica gel (eluting with 80:20hexanes:ethyl acetate) to provide a pale yellow oil which slowlycrystallized to afford 24.6 g of tert-butyl 2-iodoethylcarbamate as ayellow solid.

Part L

Solid cesium carbonate (18.33 g, 56.22 mmol) was added to a solution of2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (10.7 g, 37.5mmol), prepared in Parts A-I, in DMF (185 mL). tert-Butyl2-iodoethylcarbamate (11.17 g, 41.2 mmol), prepared in Parts J and K,was added, and the reaction mixture was heated at 65° C. for 18 hours.The solvent was removed under reduced pressure, and the residue waspartitioned between dichloromethane and water. The organic fraction waswashed with water (4×100 mL) and brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure to provide a black oil.The oil was purified by column chromatography on silica gel (elutingwith 98:2 dichloromethane:methanol) to yield 14.6 g of tert-butyl[2-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamateas a tan, waxy solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.57(d, J=2.5 Hz, 1H), 7.36 (dd, J=8.9, 2.8 Hz, 1H), 7.10 (t, J=5.6 Hz, 1H),4.84 (s, 2H), 4.64 (at, J=8.1 Hz, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.57 (q,J=7.0 Hz, 2H), 3.41 (q, J=5.8 Hz, 2H), 1.93 (sextet, J=7.8 Hz, 2H), 1.39(s, 9H), 1.16 (t, J=6.8 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H).

Part M

mCPBA (60% pure, 12.76 g, 44.36 mmol) was added in one portion to asolution of tert-butyl[2-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate(14.4 g, 33.6 mmol) and chloroform (150 mL); the reaction mixture wasstirred for 30 minutes. The reaction mixture was then poured intosaturated aqueous sodium carbonate (100 mL) and stirred for 30 minutes.Chloroform (250 mL) was added, and the organic fraction was washedsequentially with 5% aqueous sodium carbonate, water, and brine; driedover magnesium sulfate; filtered; and concentrated under reducedpressure. The resulting red oil was triturated with ethyl acetate toprovide 9.7 g of tert-butyl2-[(2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamateas a peach-colored powder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.71 (d, J=9.3 Hz, 1H), 7.56(d, J=2.7 Hz, 1H), 7.43 (dd, J=9.5, 2.3 Hz, 1H), 7.11 (t, J=5.6 Hz, 1H),4.81 (s, 2H), 4.62 (at, J=7.8 Hz, 2H), 4.24 (t, J=5.6 Hz, 2H), 3.58 (q,J=6.9 Hz, 2H), 3.41 (q, J=5.8 Hz, 2H), 1.92 (sextet, J=7.6 Hz, 2H), 1.39(s, 9H), 1.17 (t, J=6.8 Hz, 3H), 1.03 (t, J=7.6 Hz, 3H).

Part N

Ammonium hydroxide (50 mL) was added to a solution of tert-butyl2-[(2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate(9.7 g, 22 mmol) in dichloromethane (120 mL), and the mixture was cooledto 10° C. p-Toluenesulfonyl chloride (4.16 g, 21.8 mmol) was added insmall portions, while maintaining the reaction temperature below 15° C.The reaction was stirred for 16 hours; a tan precipitate formed.Dichloromethane (500 mL) was added, and the precipitate was isolated byfiltration and washed with diethyl ether to provide 3.98 g of tert-butyl[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamateas a fine powder. The organic layer was washed sequentially withammonium hydroxide, water, and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resulting solidwas recrystallized from acetonitrile to provide 4.4 g of tert-butyl2-[(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamateas a peach-colored powder.

¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=8.8 Hz, 1H), 7.38 (d, J=2.6 Hz,1H), 7.12 (dd, J=9.4, 2.5 Hz, 1H), 7.04 (t, J=5.3 Hz, 1H), 6.34 (s, 2H),4.78 (s, 2H), 4.54 (at, J=7.9 Hz, 2H), 4.09 (t, J=5.9 Hz, 2H), 3.56 (q,J=7.1 Hz, 2H), 3.35 (q, J=5.8 Hz, 2H), 1.90 (sextet, J=7.7 Hz, 2H), 1.39(s, 9H), 1.16 (t, J=6.9 Hz, 3H), 1.02 (t, J=7.3 Hz, 3H).

Part O

A solution of hydrogen chloride (55 mL of 1.2 M) in ethanol was added totert-butyl2-[(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate(3.98 g, 8.97 mmol), and the reaction was heated at reflux for one hour.The reaction mixture was allowed to cool to ambient temperature, and thesolvent was removed under reduced pressure. The resulting yellow solidwas dissolved in a small volume of water, and 10% aqueous sodiumhydroxide was added to adjust to pH 13. The mixture was then extractedwith dichloromethane (3×100 mL), and the combined extracts were washedsequentially with water and brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The resulting solid wasrecrystallized from acetonitrile to provide 2.63 g of8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas fine, peach-colored needles, mp 157-159° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=8.7 Hz, 1H), 7.39 (d, J=2.4 Hz,1H), 7.14 (dd, J=9.2, 2.8 Hz, 1H), 6.32 (s, 2H), 4.77 (s, 2H), 4.55-4.50(m, 2H), 4.04 (t, J=5.6 Hz, 2H), 3.56 (q, J=7.1 Hz, 2H), 2.94 (t, J=6.0Hz, 2H), 1.91 (sextet, J=7.5 Hz, 2H), 1.59 (s, 2H), 1.16 (t, J=6.9 Hz,3H), 1.04 (t, J=7.6 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 153.3, 150.5, 148.9, 140.0, 132.7, 127.6,126.6, 117.1, 114.6, 102.3, 70.6, 65.3, 64.2, 46.8, 41.1, 23.3, 14.9,10.8;

MS (APCI) m/z 344.2081 (344.2087 calcd for C₁₈H₂₅N₅O₂, M+H).

Anal. Calcd. for C₁₈H₂₅N₅O₂: % C, 62.95; % H, 7.34; % N, 20.39. Found: %C, 62.68; % H, 7.22; % N, 20.26.

Example 3N-[2-(4-Amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]methanesulfonamide

Methanesulfonic anhydride (0.265 g, 1.52 mmol) was added in one portionto a solution of8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction wasstirred for 30 minutes. A precipitate formed. Aqueous sodium hydroxide(25 mL of 10%) was added, and the mixture was stirred for 20 minutes.The aqueous layer was separated and extracted with dichloromethane. Thecombined organic fractions were washed sequentially with water andbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting white solid was purified by columnchromatography on silica gel (eluting with a dichloromethane:methanolranging in ratios from 97:3 to 94:6) and then recrystallized fromacetonitrile to yield 0.302 g ofN-[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]methanesulfonamideas white, granular crystals, mp 178-179.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.57 (d, J=8.8 Hz, 1H), 7.39 (d, J=3.2 Hz,1H), 7.33 (t, J=5.8 Hz, 1H), 7.15 (dd, J=9.2, 2.8 Hz, 1H), 6.36 (s, 2H),4.77 (s, 2H), 4.56-4.51 (m, 2H), 4.17 (t, J=5.6 Hz, 2H), 3.56 (q, J=6.9Hz, 2H), 3.40 (q, J=5.6 Hz, 2H), 2.98 (s, 3H), 1.91 (m, 2H), 1.16 (t,J=6.9 Hz, 3H), 1.03 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 152.7, 150.6, 148.9, 140.1, 132.7, 127.6,126.7, 117.0, 114.6, 102.6, 67.3, 65.3, 64.2, 46.7, 41.9, 23.3, 14.9,10.8;

MS (APCI) m/z 422.1850 (422.1862 calcd for C₁₉H₂₇N₅O₄S, M+H).

Anal. Calcd. for C₁₉H₂₇N₅O₄S: % C, 54.14; % H, 6.46; % N, 16.61; % S,7.61. Found: % C, 54.19; % H, 6.65; % N, 16.26; % S, 7.81.

Example 4N-(2-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)morpholine-4-carboxamide

4-Morpholinecarbonyl chloride (0.177 mL, 1.52 mmol) was added dropwiseto a solution of8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.46 mmol) in dichloromethane, and the reaction was stirredfor ten minutes. Triethylamine (0.418 mL, 3.00 mmol) was then added, andthe reaction was stirred for 16 hours. Aqueous sodium hydroxide (50%)was added, and the mixture was stirred for 30 minutes and then dilutedwith dichloromethane (100 mL). The organic layer was separated, washedsequentially with water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue was thentreated with concentrated hydrochloric acid and water. A precipitateformed and was isolated by filtration, washed with water and diethylether, and dried in a vacuum oven at 60° C. to provide 0.180 g ofN-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)morpholine-4-carboxamidehydrochloride as a white solid, mp 200-202° C. ¹H NMR (300 MHz, DMSO-d₆)δ 13.47 (s, 1H), 8.71 (bs, 2H), 7.79 (d, J=9.4 Hz, 1H), 7.54 (d, J=2.5Hz, 1H), 7.40 (dd, J=9.3, 2.5 Hz, 1H), 6.84 (t, J=5.4 Hz, 1H), 4.84 (s,2H), 4.65 (t, J=7.8 Hz, 2H), 4.19 (t, J=6.1 Hz, 2H), 3.59 (q, J=7.0 Hz,2H), 3.52 (t, J=4.7 Hz, 4H), 3.50-3.40 (m, 2H), 3.26 (t, J=4.9 Hz, 4H),1.90 (sextet, J=7.4 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.3 Hz,3H);

MS (APCI) m/z 457.2557 (457.2563 calcd for C₂₃H₃₂N₆O₄, M+H).

Anal. Calcd. for C₂₃H₃₂N₆O₄.1.0HCl.1.0H₂O: % C, 54.06; % H, 6.90; % N,16.45; % Cl, 6.94. Found: % C, 54.36; % H, 6.74; % N, 16.57; % Cl, 6.99.

The acidic filtrate was cooled to 0° C. and adjusted to pH 13 with theaddition of 50% aqueous sodium hydroxide; the resulting opaque solutionwas extracted with dichloromethane. The combined extracts were washedwith water and brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The resulting white solid was triturated withhot acetonitrile and isolated by filtration to yield 0.114 g ofN-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)morpholine-4-carboxamideas a white powder, mp 203-208° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=9.2 Hz, 1H), 7.41 (d, J=2.3 Hz,1H), 7.14 (dd, J=9.2, 2.9 Hz, 1H), 6.79 (t, J=5.2 Hz, 1H), 6.33 (s, 2H),4.77 (s, 2H), 4.57-4.52 (m, 2H), 4.12 (t, J=6.0 Hz, 2H), 3.59-3.42 (m,7H), 3.28-3.24 (m, 5H), 1.97-1.81 (m, 2H), 1.16 (t, J=7.1 Hz, 3H), 1.02(t, J=7.5 Hz, 3H).

Anal. Calcd. for C₂₃H₃₂N₆O₄.0.25H₂O: % C, 59.92; % H, 7.11; % N, 18.23.Found: % C, 59.99; % H, 7.10; % N, 18.15.

Example 5N-(2-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)-2-methylpropanamidehydrochloride

Isobutyryl chloride (0.160 mL, 1.53 mmol) was added dropwise to asolution of8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction wasstirred for 16 hours. A precipitate formed, and dichloromethane (10 mL)was added. The precipitate was isolated by filtration, washed withdichloromethane (20 mL) and diethyl ether (75 mL), and dried for onehour under reduced pressure to provide 0.511 g ofN-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)-2-methylpropanamidehydrochloride as an off-white solid, mp 240-242° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.89 (s, 1H), 8.73 (bs, 2H), 8.06 (t, J=5.4Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.40 (dd,J=8.9, 2.1 Hz, 1H), 4.84 (s, 2H), 4.67-4.61 (m, 2H), 4.18 (t, J=5.9 Hz,2H), 3.59 (q, J=6.8 Hz, 2H), 3.48 (q, J=5.6 Hz, 2H), 2.41 (septet, J=6.9Hz, 1H), 1.91 (sextet, J=7.3 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H), 1.04 (t,J=7.4 Hz, 3H), 1.00 (d, J=6.9 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 176.5, 155.3, 152.1, 148.1, 134.9, 128.4,124.7, 120.2, 119.3, 113.2, 104.2, 66.8, 65.6, 63.8, 47.1, 37.8, 33.9,23.1, 19.5, 14.9, 10.6;

MS (APCI) m/z 414.2499 (414.2505 calcd for C₂₂H₃₁N₅O₃, M+H).

Anal. Calcd. for C₂₂H₃₁N₅O₃.1.0HCl: % C, 58.72; % H, 7.17; % N, 15.56; %Cl, 7.88.

Found: % C, 58.51; % H, 7.40; % N, 15.56; % Cl, 7.88.

Example 6N-(2-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)tetrahydrofuran-2-carboxamide

A solution of8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.46 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.282 g, 2.90 mmol) in dichloromethane (15 mL) was cooled to 0° C. Asolution of tetrahydro-2-furoic acid (0.168 g, 1.45 mmol) indichloromethane (5 mL) and triethylamine (0.811 mL, 5.82 mmol) weresequentially added. The reaction was stirred at 0° C. for 30 minutes,allowed to warm to ambient temperature, stirred for two hours, andpoured into water. The aqueous layer was extracted with dichloromethane.The combined organic fractions were washed sequentially with water (2×)and brine, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluting with dichloromethane:methanolranging in ratios from 99:1 to 96:4) to provide the desired product anda bis amide by-product. The bis amide by-product was treated with 1Naqueous hydrochloric acid, heated at reflux for 1.5 hours, and cooled to0° C. The mixture was adjusted to pH 13 with the addition of 10% aqueoussodium hydroxide and extracted with dichloromethane. The combinedextracts were washed with water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure to provide a yellowoil. The oil and the previously recovered amide were combined andrecrystallized from acetonitrile to provide 0.220 g ofN-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)tetrahydrofuran-2-carboxamideas a tan, crystalline solid, mp 202.5-204.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (t, J=5.5 Hz, 1H), 7.55 (d, J=8.5 Hz,1H), 7.39 (d, J=2.7 Hz, 1H), 7.13 (dd, J=9.3, 2.5 Hz, 1H), 6.34 (s, 2H),4.77 (s, 2H), 4.56-4.51 (m, 2H), 4.25-4.21 (m, 1H), 4.14 (t, J=6.0 Hz,2H), 3.91-3.84 (m, 1H), 3.79-3.72 (m, 1H), 3.56 (q, J=6.9 Hz, 2H),3.54-3.48 (m, 2H), 2.17-2.05 (m, 1H), 1.96-1.69 (m, 5H), 1.16 (t, J=6.8Hz, 3H), 1.02 (t, J=7.5 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 172.8, 152.9, 150.6, 148.9, 140.1, 132.7,127.6, 126.7, 117.1, 114.6, 102.5, 77.7, 68.5, 66.2, 65.3, 64.2, 46.7,37.7, 29.9, 24.8, 23.3, 14.9, 10.7;

MS (APCI) m/z 442.2459 (442.2454 calcd for C₂₃H₃₁N₅O₄, M+H).

Anal. Calcd. for C₂₃H₃₁N₅O₄: % C, 62.57; % H, 7.08; % N, 15.86. Found: %C, 62.47; % H, 7.14; % N, 15.91.

Example 7 tert-Butyl3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate

Part A

7-Benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (60.3g, 0.188 mol), prepared as described in Parts A-G of Example 1, and 10%palladium on carbon (10 g) were mixed with ethanol (500 mL). Ammoniumformate (101.53 g, 1.61 mol) and ethanol (500 mL) were then added, andthe reaction mixture was heated at reflux for two hours. The mixture wasallowed to cool to ambient temperature slowly and stirred overnight. Thereaction mixture was filtered through a layer of CELITE filter aid, andthe filter cake was washed with ethanol (1 L), methanol (2 L) anddichloromethane (2 L). The combined filtrates were concentrated underreduced pressure to provide a tan solid, which was triturated with coldethanol and isolated by filtration to yield 30 g of1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol as a tan,granular solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.00 (s, 1H), 8.12 (d, J=9.3Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.23 (dd, J=9.3, 2.5 Hz, 1H), 4.36 (d,J=7.4 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.25-2.10 (m, 1H), 1.88 (sextet,J=7.4 Hz, 2H), 1.03 (t, J=7.5 Hz, 3H), 0.92 (d, J=7.1 Hz, 6H).

Part B

The general methods described in Parts J and K of Example 2 were used toprepare 16.2 g of tert-butyl 3-iodopropylcarbamate from3-amino-1-propanol (6.55 g, 8.72 mmol); the product was isolated as ayellow solid.

Part C

A modification of the general method described in Part L of Example 2was used to treat1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol withtert-butyl 3-iodopropylcarbamate. The reaction mixture was diluted withwater; a precipitate formed. The precipitate was isolated by filtration,washed with water and then with diethyl ether until the filtrate wasclear, and dried overnight in a vacuum oven at 60° C. to yieldtert-butyl3-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamateas a tan powder.

¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.19 (d, J=9.3 Hz, 1H), 7.54(d, J=2.6 Hz, 1H), 7.33 (dd, J=8.9, 2.9 Hz, 1H), 6.99-6.86 (m, 1H), 4.40(d, J=8.0 Hz, 2H), 4.15 (t, J=6.3 Hz, 2H), 3.14 (q, J=6.4 Hz, 2H), 2.92(t, J=7.6 Hz, 2H), 2.27-2.09 (m, 1H), 1.98-1.80 (m, 4H), 1.38 (s, 9H),1.04 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.1 Hz, 6H).

Part D

The general methods described in Parts M and N of Example 2 were used toconvert tert-butyl3-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamateto tert-butyl3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate,which was isolated as off-white crystals, mp 162.5-164° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=8.9 Hz, 1H), 7.04 (d, J=2.6 Hz,1H), 6.94-6.88 (m, 1H), 6.89 (dd, J=9.2, 2.8, Hz, 1H), 6.36 (s, 2H),4.28 (d, J=7.5 Hz, 2H), 4.04 (t, J=6.2 Hz, 2H), 3.11 (q, J=6.5 Hz, 2H),2.86 (t, J=7.5 Hz, 2H), 2.2-2.09 (m, 1H), 1.91-1.77 (m, 4H), 1.38 (s,9H), 1.01 (t, J=7.2 Hz, 3H), 0.91 (d, J=6.2 Hz, 6H);

MS (APCI) m/z 456.2960 (456.2975 calcd for C₂₅H₃₇N₅O₃, M+H).

Anal. Calcd. for C₂₅H₃₇N₅O₃: % C, 65.91; % H, 8.19; % N, 15.37. Found: %C, 65.65; % H, 8.18; % N, 15.19.

Example 87-(3-Aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine

A modification of the general method described in Part O of Example 2was used to deprotect tert-butyl3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate. A precipitate formed in theaqueous mixture at pH 13 and was isolated by filtration to provide7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 173-174° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.4 Hz, 1H), 7.06 (d, J=3.2 Hz,1H), 6.89 (dd, J=8.8, 2.5 Hz, 1H), 6.35 (s, 2H), 4.28 (d, J=7.5 Hz, 2H),4.10 (t, J=6.7 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.72 (t, J=6.8 Hz, 2H),2.2-2.08 (m, 1H), 1.90-1.77 (m, 4H), 1.6 (b s, 2H), 1.02 (t, J=7.6 Hz,3H), 0.91 (d, J=6.8 Hz, 6H);

MS (APCI) m/z 356.2464 (356.2450 calcd for C₂₀H₂₉N₅O, M+H).

Anal. Calcd. for C₂₀H₂₉N₅O: % C, 67.58; % H, 8.22; % N, 19.70. Found: %C, 67.25; % H, 7.94; % N, 19.75.

Example 9 tert-Butyl2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate

Part A

The preparation of 7-benzyloxy-N⁴-(2-methylpropyl)quinoline-3,4-diamineis described in Parts A-F of Example 1. Under a nitrogen atmosphere,triethyl orthoacetate (4.59 mL, 25.0 mmol) was added to a solution of7-benzyloxy-N⁴-(2-methylpropyl)quinoline-3,4-diamine (8.05 g, 25.0 mmol)in xylenes (130 mL), and the resulting solution was heated at reflux(160° C.) overnight. The solvent volume was reduced to 70 mL using aDean-Stark trap. Over a period of a few days, a precipitate formed.Diethyl ether was added, and the precipitate was isolated by filtrationand washed with diethyl ether to provide 6.81 g of7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as alight-brown powder.

Part B

The method described in Part J of Example 1 was used to convert7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline to2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol, which wasobtained as a solid, mp>250° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.97 (s, 1H), 8.12 (d, J=9.2Hz, 1H), 7.42 (d, J=2.6 Hz, 1H), 7.25 (dd, J=8.9, 2.8 Hz, 1H), 4.35 (d,J=7.6 Hz, 2H), 2.61 (s, 3H), 2.19 (septet, J=6.9 Hz, 1H), 0.94 (d, J=6.7Hz, 6H);

MS (APCI) m/z 256.2 (256.3 calcd for C₁₅H₁₇N₃O, M+H).

Anal. Calcd. for C₁₅H₁₇N₃O: % C, 70.56; % H, 6.71; % N, 16.46. Found: %C, 70.33; % H, 6.66; % N, 16.35.

Part C

tert-Butyl 2-iodoethylcarbamate (2.55 g, 9.41 mmol), prepared asdescribed in Parts J and K of Example 2, was added to a mixture of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (2.00 g, 7.83mmol) and cesium carbonate (3.83 g, 11.7 mmol) in DMF (30 mL), and thereaction was heated at 60° C. for four hours. The solvent was removedunder reduced pressure, and the resulting solid was triturated withwater and isolated by filtration to yield 2.57 g of tert-butyl2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas a light-brown solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.55(d, J=2.9 Hz, 1H), 7.34 (dd, J=9.1, 2.8 Hz, 1H), 7.07-7.02 (m, 1H), 4.39(d, J=8.0 Hz, 2H), 4.14 (t, J=5.5 Hz, 2H), 3.38 (q, J=5.9 Hz, 2H), 2.63(s, 3H), 2.28-2.11 (m, 1H), 1.39 (s, 9H), 0.94 (d, J=6.4 Hz, 6H).

Part D

The general methods described in Parts M and N of Example 2 werefollowed using tert-butyl2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas the starting material. The crude product was recrystallized fromethanol to yield 1.29 g of tert-butyl2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas a yellow-orange solid, mp 226.9-228.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.5 Hz,1H), 7.01 (t, J=5.9 Hz, 1H), 6.90 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (s, 2H),4.27 (d, J=7.6 Hz, 2H), 4.03 (t, J=5.9 Hz, 2H), 3.36-3.28 (m, 2H), 2.56(s, 3H), 2.16 (m, 1H), 1.39 (s, 9H), 0.93 (d, J=6.9 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.0, 155.7, 151.9, 149.2, 146.5, 132.8,125.0, 121.1, 111.4, 109.1, 108.2, 77.7, 66.1, 51.6, 28.8, 28.2, 19.2,13.9;

MS (APCI) m/z 414.2507 (414.2505 calcd for C₂₁H₃₁N₅O₃, M+H).

Anal. Calcd. for C₂₁H₃₁N₅O₃: % C, 63.90; % H, 7.56; % N, 16.94. Found: %C, 63.74; % H, 7.41; % N, 16.80.

Example 107-(2-Aminoethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

The general method described in Part O of Example 2 was used to converttert-butyl2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(1.29 g, 3.12 mmol) to 1.1 g of7-(2-aminoethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,isolated as a white powder. The product was not recrystallized.

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.6 Hz,1H), 6.91 (dd, J=9.4, 2.5 Hz, 1H), 6.40 (s, 2H), 4.27 (d, J=7.4 Hz, 2H),4.00 (t, J=5.8 Hz, 2H), 2.92 (t, J=5.9 Hz, 2H), 2.56 (s, 3H), 2.23-2.09(m, 1H), 1.94 (bs, 2H), 0.93 (d, J=7.1 Hz, 6H).

Example 11N-{3-[4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}methanesulfonamide

Methanesulfonic anhydride (0.245 g, 1.41 mmol) was added in one portionto a suspension of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 18hours. Saturated aqueous sodium bicarbonate was added, and the reactionwas stirred for 20 minutes. The aqueous layer was separated andextracted with chloroform. The combined organic fractions were washedwith water and brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting off-white solid wasdissolved in concentrated hydrochloric acid; the solution was thencooled to 0° C. and adjusted to pH 13 with the addition of 50% aqueoussodium hydroxide. The opaque solution was extracted withdichloromethane. The extract was washed sequentially with water andbrine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The resulting solid was recrystallized fromacetonitrile to yield 0.160 g ofN-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}methanesulfonamideas a flocculent, white solid, mp 166.5-168.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=8.6 Hz, 1H), 7.085 (t, J=5.5 Hz,1H), 7.06 (d, J=3.3 Hz, 1H), 6.91 (dd, J=8.7, 2.5 Hz, 1H), 6.37 (s, 2H),4.29 (d, J=7.3 Hz, 2H), 4.11 (t, J=6.3 Hz, 2H), 3.14 (q, J=6.4 Hz, 2H),2.90 (s, 3H), 2.86 (t, J=7.5 Hz, 2H), 2.14 (septet, J=7.0 Hz, 1H), 1.95(quintet, J=6.6 Hz, 2H), 1.83 (sextet, J=7.3 Hz, 2H), 1.02 (t, J=7.6 Hz,3H), 0.91 (d, J=7.1 Hz, 6H);

¹³C NMR (125 MHz, DMSO-d₆) δ 157.1, 152.6, 151.8, 146.2, 132.8, 125.1,121.2, 111.6, 109.0, 108.0, 64.7, 51.2, 39.4, 39.2, 29.3, 28.7, 28.5,20.9, 19.1, 13.8;

MS (APCI) m/z 434.2235 (434.2226 calcd for C₂₁H₃₁N₅O₃S, M+H).

Anal. Calcd. for C₂₁H₃₁N₅O₃S: % C, 58.18; % H, 7.21; % N, 16.15; % S,7.40. Found: % C, 57.87; % H, 7.56; % N, 16.02; % S, 7.72.

Example 12N-{2-[4-Amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}methanesulfonamide

The general method described in Example 11 was used to convert7-(3-aminopropoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amineto 0.014 g ofN-{2-[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}methanesulfonamide,which was obtained as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (d, J=9.6 Hz, 1H), 7.32 (t, J=5.6 Hz,1H), 7.12 (d, J=2.5 Hz, 1H), 6.99 (dd, J=9.3, 2.6 Hz, 1H), 6.92 (s, 2H),4.30 (d, J=7.6 Hz, 2H), 4.13 (t, J=5.7 Hz, 2H), 3.39 (q, J=5.6 Hz, 2H),2.97 (s, 3H), 2.58 (s, 3H), 2.24-2.08 (m, 1H), 0.93 (d, J=6.9 Hz, 6H);

MS (APCI) m/z 392.1758 (392.1756 calcd for C₁₈H₂₅N₅O₃S, M+H).

Example 137-[3-(1,1-Dioxidoisothiazolidin-2-yl)propoxy]-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine

3-Chloropropanesulfonyl chloride (0.206 mL, 1.69 mmol) was addeddropwise to a suspension of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.41 mmol) in chloroform (17 mL), and the reaction was stirredfor 30 minutes. The solvent was removed under reduced pressure, and theresidue was dissolved in DMF (17 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene(0.316 mL, 2.11 mmol) was then added, and the reaction was stirred for18 hours. The reaction was poured into water, and the mixture wasextracted twice with dichloromethane. The combined organic fractionswere washed sequentially with water and brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluting with 97:3dichloromethane:methanol) followed by recrystallization fromacetonitrile to provide 0.237 g of7-[3-(1,1-dioxidoisothiazolidin-2-yl)propoxy]-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amineas needle-like, white crystals, mp 142-144° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=9.1 Hz, 1H), 7.05 (d, J=2.6 Hz,1H), 6.91 (dd, J=9.0, 2.6 Hz, 1H), 6.37 (s, 2H), 4.29 (d, J=7.4 Hz, 2H),4.10 (t, J=6.2 Hz, 2H), 3.26-3.17 (m, 4H), 3.09 (t, J=7.0 Hz, 2H), 2.86(at, J=7.5 Hz, 2H), 2.28-1.96 (m, 5H), 1.84 (sextet, J=7.5 Hz, 2H), 1.02(t, J=7.3 Hz, 3H), 0.91 (d, J=6.6 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.0, 152.6, 151.9, 146.5, 132.8, 125.1,121.2, 111.5, 109.0, 108.2, 64.8, 51.2, 46.8, 46.1, 41.3, 28.7, 28.6,27.3, 20.9, 19.1, 18.3, 13.8;

MS (APCI) m/z 460.2391 (460.2382 calcd for C₂₃H₃₃N₅O₃S, M+H).

Anal. Calcd. for C₂₃H₃₃N₅O₃S: % C, 60.11; % H, 7.24; % N, 15.24; % S,6.98. Found: % C, 59.52; % H, 7.23; % N, 15.16; % S, 6.80.

Example 14N-(3-{[4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamide

2-(1-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added inone portion to a suspension of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. Thereaction mixture was poured into saturated aqueous sodium carbonate. Theorganic layer was separated, washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The resulting pale yellow oil was purified by column chromatography onsilica gel (eluting with dichloromethane:methanol ranging in ratios from99:1 to 94:6) and subsequent recrystallization from acetonitrile toyield 0.341 g ofN-(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamideas white crystals, mp 164-168° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (ad, J=7.9 Hz, 1H), 7.96-7.92 (m, 1H),7.85-7.75 (m, 2H), 7.61-7.49 (m, 2H), 7.43-7.33 (m, 3H), 7.08 (d, J=2.4Hz, 1H), 6.89 (dd, J=9.2, 2.9 Hz, 1H), 6.38 (s, 2H), 4.28 (d, J=7.6 Hz,2H), 4.14 (t, J=6.2 Hz, 2H), 3.47-3.31 (m, 4H), 3.22 (q, J=6.4 Hz, 2H),2.86 (t, J=7.5 Hz, 2H), 2.21-2.06 (m, 1H), 1.99 (quintet, J=6.7 Hz, 2H),1.84 (septet, J=7.3 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H), 0.91 (d, J=6.5 Hz,6H);

MS (APCI) m/z 574.2847 (574.2852 calcd for C₃₂H₃₉N₅O₃S, M+H).

Anal. Calcd. for C₃₂H₃₉N₅O₃S: % C, 66.99; % H, 6.85; % N, 12.21. Found:% C, 66.67; % H, 6.98; % N, 12.22.

Example 15N-{3-[4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}-2-methylpropanamide

A solution of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.41 mmol) in chloroform (15 mL) was cooled to 0° C.Isobutyryl chloride (0.147 mL, 1.40 mmol) was added dropwise, and thereaction was stirred for 30 minutes. The reaction was diluted withchloroform and poured into 3% aqueous sodium carbonate. The organiclayer was separated, washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting white solid was recrystallized from acetonitrile to yield0.450 g ofN-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}-2-methylpropanamideas feathery, white crystals, mp 179-181° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=9.1 Hz, 1H), 7.80 (t, J=5.3 Hz,1H), 7.04 (d, J=2.4 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.36 (s, 2H),4.28 (d, J=7.6 Hz, 2H), 4.05 (t, J=6.5 Hz, 2H), 3.22 (q, J=6.4 Hz, 2H),2.86 (t, J=7.5 Hz, 2H), 2.34 (quintet, J=6.9 Hz, 1H), 2.20-2.08 (m, 1H),1.93-1.77 (m, 4H), 1.02 (t, J=7.6 Hz, 3H), 1.00 (d, J=6.9 Hz, 6H), 0.91(d, J=6.6 Hz, 6H);

MS (APCI) m/z 426.2871 (426.2869 calcd for C₂₄H₃₅N₅O₂, M+H).

Anal. Calcd. for C₂₄H₃₅N₅O₂: % C, 67.74; % H, 8.29; % N, 16.46. Found: %C, 67.93; % H, 8.14; % N, 16.49.

Example 16N-{3-[4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}nicotinamide

Nicotinoyl chloride hydrochloride (0.23 g, 1.29 mmol) was added in oneportion to a solution of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.460 g, 1.29 mmol) and triethylamine (0.383 mL, 2.75 mmol) inchloroform (15 mL), and the reaction was stirred for 16 hours. Thereaction mixture was poured into saturated aqueous sodium bicarbonateand stirred for 30 minutes. The aqueous layer was separated andextracted with chloroform. The combined organic fractions were washedsequentially with water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resulting paleyellow oil was triturated with acetonitrile, which was removed underreduced pressure. The resulting solid was recrystallized fromacetonitrile to yield 0.310 g ofN-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}nicotinamideas off-white, granular crystals, mp 172-174° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (d, J=2.5 Hz, 1H), 8.77 (t, J=5.7 Hz,1H), 8.70 (dd, J=5.0, 1.3 Hz, 1H), 8.19 (dt, J=8.1, 1.7 Hz, 1H), 7.86(d, J=8.9 Hz, 1H), 7.52-7.47 (m, 1H), 7.07 (d, J=2.6 Hz, 1H), 6.91 (dd,J=8.9, 2.8 Hz, 1H), 6.37 (s, 2H), 4.29 (d, J=7.6 Hz, 2H), 4.14 (t, J=5.9Hz, 2H), 3.49 (q, J=6.1 Hz, 2H), 2.86 (t, J=7.8 Hz, 2H), 2.21-1.95 (m,3H), 1.84 (sextet, J=7.4 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H), 0.91 (d, J=6.1Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 164.8, 157.1, 152.5, 151.9, 151.7, 148.3,146.5, 134.9, 132.8, 130.0, 125.1, 123.4, 121.2, 111.5, 109.0, 108.2,65.2, 51.2, 36.4, 28.7, 28.5, 20.9, 19.1, 13.8;

MS (APCI) m/z 461.2655 (461.2665 calcd for C₂₆H₃₂N₆O₂, M+H).

Anal. Calcd. for C₂₆H₃₂N₆O₂.0.5H₂O: % C, 66.50; % H, 7.08; % N, 17.90.Found: % C, 66.62; % H, 7.18; % N, 18.08.

Example 17N-{2-[4-Amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}-2-methylpropanamide

The method described in Example 15 was used to convert7-(2-aminoethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amineto 0.170 g ofN-{2-[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}-2-methylpropanamide,which was isolated as flocculent, white crystals, mp 205-206° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (t, J=5.2 Hz, 1H), 7.88 (d, J=9.1 Hz,1H), 7.07 (d, J=3.0 Hz, 1H), 6.89 (dd, J=8.9, 2.8 Hz, 1H), 6.50 (s, 2H),4.27 (d, J=7.5 Hz, 2H), 4.06 (t, J=5.7 Hz, 2H), 3.45 (q, J=5.6 Hz, 2H),2.56 (s, 3H), 2.39 (m, 1H), 2.16 (septet, J=6.7 Hz, 1H), 1.00 (d, J=6.9Hz, 6H), 0.93 (d, J=6.3 Hz, 6H);

MS (APCI) m/z 456.2960 (456.2975 calcd for C₂₁H₂₉N₅O₂, M+H).

Anal. Calcd. for C₂₁H₂₉N₅O₂: % C, 65.77; % H, 7.62; % N, 18.26. Found: %C, 65.42; % H, 7.88; % N, 17.96.

Example 181-{2-[4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}pyrrolidin-2-one

Part A

A mixture of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol(0.500 g, 1.76 mmol), triphenylphosphine (0.462 g, 1.76 mmol), and1-(2-hydroxyethyl)pyrrolidin-2-one (0.200 mL, 1.77 mmol) in THF (17 mL)was cooled to 0° C. Diethyl azodicarboxylate (0.277 mL) was addeddropwise, and the reaction mixture was allowed to warm to ambienttemperature and stirred for 19 hours. Solid unreacted1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (0.150 g,0.42 mmol) was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluting with 98:2dichloromethane:methanol) to provide 0.456 g of1-{2-[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}pyrrolidin-2-onean off-white, waxy solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.20 (d, J=9.2 Hz, 1H), 7.58(d, J=2.4 Hz, 1H), 7.35 (dd, J=9.2, 2.6 Hz, 1H), 4.40 (d, J=7.4 Hz, 2H),4.27 (t, J=5.7 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.50 (at, J=7.1 Hz, 2H),2.92 (t, J=7.6 Hz, 2H), 2.30-2.10 (m, 3H), 1.98-1.83 (m, 4H), 1.04 (t,J=7.5 Hz, 3H), 0.92 (d, J=6.2 Hz, 6H).

Part B

The general methods described in Parts M and N of Example 2 were used toconvert the material from Part A to 0.120 g of1-{2-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}pyrrolidin-2-one,which was obtained as tan, granular crystals, mp 206-208° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.3 Hz,1H), 6.91 (dd, J=9.2, 2.9 Hz, 1H), 6.41 (s, 2H), 4.29 (d, J=7.5 Hz, 2H),4.16 (t, J=5.5 Hz, 2H), 3.59 (t, J=5.7 Hz, 2H), 3.48 (t, J=7.2 Hz, 2H),2.86 (t, J=7.5 Hz, 2H), 2.23 (t, J=8.0 Hz, 2H), 2.20-2.07 (m, 1H), 1.92(quintet, J=7.2 Hz, 2H), 1.84 (sextet, J=7.1 Hz, 2H), 1.02 (t, J=7.0 Hz,3H), 0.91 (d, J=6.8 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 174.1, 156.8, 152.6, 152.0, 146.4, 132.7,125.1, 121.3, 111.5, 109.2, 108.2, 65.4, 51.2, 47.3, 41.4, 30.3, 28.7,28.5, 20.9, 19.1, 17.6, 13.8;

MS (APCI) m/z 410.2541 (410.2556 calcd for C₂₃H₃₁N₅O₂, M+H).

Anal. Calcd. for C₂₃H₃₁N₅O₂: % C, 67.46; % H, 7.63; % N, 17.10. Found: %C, 67.28; % H, 7.53; % N, 17.16.

Example 19N-(2-{[4-Amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)morpholine-4-carboxamide

A suspension of7-(2-aminoethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.300 g, 0.958 mmol) in chloroform (10 mL) was cooled to 0° C.4-Morpholinecarbonyl chloride (0.110 mL, 0.942 mmol) was added dropwise,and the reaction was stirred for five minutes at 0° C. The reaction wasthen allowed to warm to ambient temperature over a period of 15 minutes,and the solvent was removed under reduced pressure. The resultingoff-white solid was dissolved in dichloromethane. The solution waswashed sequentially with 10% aqueous sodium hydroxide, water, and brine;dried over magnesium sulfate; filtered; and concentrated under reducedpressure. The residue was recrystallized from acetonitrile to provide0.150 g ofN-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)morpholine-4-carboxamideas a white powder, mp 215-219° C. (decomposition).

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.6 Hz,1H), 6.91 (dd, J=9.1, 2.7 Hz, 1H), 6.77 (t, J=5.3 Hz, 1H), 6.42 (s, 2H),4.27 (d, J=7.5 Hz, 2H), 4.07 (t, J=5.8 Hz, 2H), 3.53 (t, J=5.0 Hz, 4H),3.44 (q, J=5.8 Hz, 2H), 3.27 (t, J=5.1 Hz, 4H), 2.56 (s, 3H), 2.16 (m,1H), 0.93 (d, J=6.3 Hz, 6H);

MS (APCI) m/z 427.2475 (427.2458 calcd for C₂₂H₃₀N₆O₃, M+H).

Anal. Calcd. for C₂₂H₃₀N₆O₃: % C, 61.95; % H, 7.09; % N, 19.70. Found: %C, 61.96; % H, 7.18; % N, 19.37.

Example 20N-(3-{[4-Amino-2-propyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)morpholine-4-carboxamide

The general method described in Example 19 was used to convert7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminetoN-(3-{[4-amino-2-propyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)morpholine-4-carboxamide,which was isolated as a white solid, mp 145° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=9.5 Hz, 1H), 7.05 (d, J=2.7 Hz,1H), 6.89 (dd, J=8.6, 2.4 Hz, 1H), 6.61 (t, J=5.2 Hz, 1H), 6.36 (s, 2H),4.28 (d, J=7.7 Hz, 2H), 4.06 (t, J=6.2 Hz, 2H), 3.53 (t, J=4.8 Hz, 4H),3.28-3.18 (m, 6H), 2.86 (t, J=7.5 Hz, 2H), 2.21-2.04 (m, 1H), 1.97-1.76(m, 4H), 1.02 (t, J=7.0 Hz, 3H), 0.91 (d, J=6.8 Hz, 6H);

MS (APCI) m/z 469.2937 (469.2927 calcd for C₂₅H₃₆N₆O₃, M+H).

Anal. Calcd. for C₂₅H₃₆N₆O₃.H₂O: % C, 61.71; % H, 7.87; % N, 17.27.Found: % C, 61.36; % H, 7.96; % N, 17.55.

Example 21N-{[(3-{[4-Amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)amino]carbonyl}-4-fluorobenzenesulfonamide

A solution of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.41 mmol) in chloroform (15 mL) was cooled to 0° C.;4-fluorobenzenesulfonyl isocyanate (0.548 g, 2.72 mmol) was added inthree portions over a period of 30 minutes. A white precipitate waspresent and was isolated by filtration, washed with chloroform, anddried overnight in a vacuum oven at 60° C. to provide 0.671 g ofN-{[(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)amino]carbonyl}-4-fluorobenzenesulfonamideas a white powder, mp 194-198° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.98-7.85 (m, 3H), 7.37 (t, J=8.7 Hz, 2H),7.07 (d, J=2.5 Hz, 1H), 6.92 (dd, J=8.7, 2.5 Hz, 1H), 6.76 (s, 2H), 6.57(s, 1H), 4.30 (d, J=7.6 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.14 (aq, J=6.2Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.22-2.05 (m, 1H), 1.91-1.77 (m, 4H),1.02 (t, J=7.3 Hz, 3H), 0.92 (d, J=6.2 Hz, 6H);

MS (APCI) m/z 557.2365 (557.2346 calcd for C₂₇H₃₃FN₆O₄S, M+H).

Anal. Calcd. for C₂₇H₃₃FN₆O₄S: % C, 58.26; % H, 5.98; % N, 15.10; % S,5.76; % F, 3.41.

Found: % C, 57.96; % H, 5.96; % N, 15.04; % S, 5.47; % F, 3.59.

Example 22 tert-Butyl4-(2-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate

Part A

The general methods described in Parts J and K of Example 2 were used toprepare tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate, which wasisolated as a yellow oil.

Part B

The general method described in Part L of Example 2 was used to treat1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol withtert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate. After the work-upprocedure, tert-butyl4-(2-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylatewas isolated as a gray-brown solid and used without purification.

¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.18 (d, J=9.4 Hz, 1H), 7.56(d, J=2.5 Hz, 1H), 7.33 (dd, J=9.0, 2.9 Hz, 1H), 4.39 (d, J=7.4 Hz, 2H),4.19 (t, J=6.2 Hz, 2H), 3.99-3.86 (m, 3H), 2.92 (t, J=7.2 Hz, 2H),2.81-2.62 (m, 2H), 2.25-2.06 (m, 1H), 1.89 (sextet, J=7.4 Hz, 2H),1.80-1.64 (m, 4H), 1.39 (s, 9H), 1.20-1.00 (m, 2H), 1.04 (t, J=7.6 Hz,3H), 0.92 (d, J=6.3 Hz, 6H).

Part C

The general methods described in Parts M and N of Example 2 were used toaminate tert-butyl4-(2-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate.The crude product was triturated with hot acetonitrile and isolated byfiltration to yield tert-butyl4-(2-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylateas an orange solid, mp 196.4-199.6° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (d, J=9.4 Hz, 1H), 7.05 (d, J=2.6 Hz,1H), 6.89 (dd, J=8.9, 2.6 Hz, 1H), 6.38 (s, 2H), 4.28 (d, J=7.5 Hz, 2H),4.09 (t, J=5.6 Hz, 2H), 3.98-3.88 (m, 2H), 2.86 (t, J=7.8 Hz, 2H),2.80-2.63 (m, 2H), 2.18-2.08 (m, 1H), 1.83 (sextet, J=7.4 Hz, 2H),1.76-1.63 (m, 5H), 1.39 (s, 9H), 1.15-1.01 (m, 2H), 1.01 (t, J=7.6 Hz,3H), 0.91 (d, J=6.3 Hz, 6H);

MS (APCI) m/z 510.3424 (510.3444 calcd for C₂₉H₄₃N₅O₃, M+H).

Anal. Calcd. for C₂₉H₄₃N₅O₃: % C, 68.34; % H, 8.50; % N, 13.74. Found: %C, 68.05; % H, 8.67; % N, 13.54.

Example 231-(2-Methylpropyl)-7-(2-piperidin-4-ylethoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine

The general method described in Part O of Example 2 was used to converttert-butyl4-(2-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylateto1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine,which was isolated as a brown solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.3 Hz, 1H), 7.04 (d, J=3.0 Hz,1H), 6.89 (dd, J=9.1, 2.8 Hz, 1H), 6.35 (s, 2H), 4.28 (d, J=6.9 Hz, 2H),4.08 (t, J=6.5 Hz, 2H), 2.97-2.88 (m, 2H), 2.86 (t, J=7.4 Hz, 2H),2.50-2.37 (m, 2H), 2.21-2.07 (m, 1H), 1.83 (sextet, J=7.4 Hz, 2H),1.70-1.50 (m, 6H), 1.18-0.97 (m, 2H), 1.02 (t, J=7.5 Hz, 3H), 0.91 (d,J=6.2 Hz, 6H);

MS (APCI) m/z 410.2918 (410.2920 calcd for C₂₄H₃₅N₅O, M+H).

Example 242-Methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

The general method described in Part L of Example 2 was used to treat2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol withtert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate. Afterchromatographic purification, tert-butyl4-(2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylatewas isolated as a viscous, orange oil.

¹H NMR (300 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.56(d, J=2.1 Hz, 1H), 7.34 (dd, J=9.2, 2.6 Hz, 1H), 4.38 (d, J=7.5 Hz, 2H),4.19 (t, J=6.3 Hz, 2H), 3.99-3.88 (m, 2H), 2.82-2.62 (m, 2H), 2.63 (s,3H), 2.19 (septet, J=6.9 Hz, 1H), 1.81-1.61 (m, 5H), 1.39 (s, 9H),1.18-0.99 (m, 2H), 0.93 (d, J=6.9 Hz, 6H).

Part B

The general methods described in Parts M and N of Example 2 were used toaminate tert-butyl4-(2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate(3.6 g, 9.8 mmol). The crude product was triturated with hotacetonitrile and isolated by filtration to yield 2.67 g of tert-butyl4-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylateas a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.3 Hz, 1H), 7.05 (d, J=2.7 Hz,1H), 6.89 (dd, J=8.6, 2.6 Hz, 1H), 6.39 (s, 2H), 4.27 (d, J=7.5 Hz, 2H),4.09 (t, J=6.0 Hz, 2H), 3.99-3.87 (m, 2H), 2.81-2.63 (m, 2H), 2.56 (s,3H), 2.24-2.08 (m, 1H), 1.80-1.60 (m, 5H), 1.39 (s, 9H), 1.18-0.98 (m,2H), 0.93 (d, J=6.6 Hz, 6H).

Part C

The general method described in Part O of Example 2 was used to convertthe material from Part B to 1.93 g of2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine,which was isolated as a tan solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=8.7 Hz, 1H), 7.04 (d, J=1.8 Hz,1H), 6.89 (d, J=8.7 Hz, 1H), 6.40 (s, 2H), 4.26 (d, J=6.9 Hz, 2H), 4.08(t, J=5.4 Hz, 2H), 3.41-3.12 (m, 2H), 3.02-2.86 (m, 2H), 2.56 (s, 3H),2.24-2.07 (m, 1H), 1.76-1.48 (m, 5H), 1.28-1.00 (m, 3H), 0.93 (d, J=6.3Hz, 6H).

Example 257-{2-[1-(Methanesulfonyl)piperidin-4-yl]ethoxy}-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

The general method described in Example 11 was used to convert2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amineto 0.150 g of7-{2-[1-(methanesulfonyl)piperidin-4-yl]ethoxy}-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,which was isolated as an off-white powder.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.3 Hz, 1H), 7.06 (d, J=2.5 Hz,1H), 6.90 (dd, J=8.5, 2.5 Hz, 1H), 6.39 (s, 2H), 4.27 (d, J=6.8 Hz, 2H),4.11 (t, J=6.3 Hz, 2H), 3.59-3.49 (m, 2H), 2.84 (s, 3H), 2.70 (ddd,J=11.9, 11.9, 1.4 Hz, 2H), 2.56 (s, 3H), 2.23-2.09 (m, 1H), 1.90-1.55(m, 5H), 1.35-1.17 (m, 2H), 0.93 (d, J=7.2 Hz, 6H).

Example 261-(4-{2-[4-Amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}piperidin-1-yl)-2-methylpropan-1-one

The general method described in Example 15 was used to convert2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amineto 0.158 g of1-(4-{2-[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}piperidin-1-yl)-2-methylpropan-1-one,which was isolated as an off-white solid, mp 205.1-207.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.3 Hz, 1H), 7.05 (d, J=2.5 Hz,1H), 6.90 (dd, J=8.6, 2.5 Hz, 1H), 6.40 (s, 2H), 4.39 (ad, J=11.7 Hz,1H), 4.27 (d, J=7.5 Hz, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.93 (ad, J=13.3Hz, 1H), 3.00 (at, J=12.4 Hz, 1H), 2.85 (septet, J=6.7 Hz, 1H), 2.56 (s,3H), 2.6-2.5 (m, 1H), 2.19 (m, 1H), 1.87-1.65 (m, 5H), 1.28-0.98 (m,8H), 0.93 (d, J=7.0 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 173.9, 157.2, 151.9, 149.2, 146.5, 132.8,124.9, 121.1, 111.5, 108.9, 108.1, 65.0, 51.6, 44.9, 41.2, 35.0, 32.7,31.6, 28.9, 28.7, 19.5, 19.4, 19.2, 13.9;

MS (APCI) m/z 452.3037 (452.3026 calcd for C₂₆H₃₇N₅O₂, M+H).

Anal. Calcd. for C₂₆H₃₇N₅O₂.0.1H₂O: % C, 68.87; % H, 8.27; % N, 15.45.Found: % C, 68.37; % H, 8.33; % N, 15.07.

Example 277-{2-[1-(Cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

The general method described in Example 15 was used to treat2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-aminewith cyclopentanecarbonyl chloride to provide 0.158 g of7-{2-[1-(cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,which was isolated as an off-white solid, mp 235.7-238.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.1 Hz, 1H), 7.05 (d, J=1.7 Hz,1H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.40 (s, 2H), 4.44-4.32 (m, 1H), 4.26(d, J=6.6 Hz, 2H), 4.12-4.08 (m, 2H), 4.0-3.92 (m, 1H), 3.04-2.90 (m,2H), 2.56 (s, 3H), 2.52-2.48 (m, 1H), 2.24-2.1 (m, 1H), 1.84-1.42 (m,13H), 1.20-0.96 (m, 2H), 0.93 (d, J=7.2 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 173.0, 157.1, 151.9, 149.2, 146.5, 132.8,124.9, 121.1, 111.5, 108.9, 108.1, 65.0, 51.6, 45.0, 41.4, 35.0, 32.7,32.5, 31.6, 29.7, 28.7, 25.6, 19.2, 13.9;

MS (APCI) m/z 478.3189 (478.3182 calcd for C₂₈H₃₉N₅O₂, M+H).

Anal. Calcd. for C₂₈H₃₉N₅O₂.0.45H₂O: % C, 69.23; % H, 8.28; % N, 14.42.Found: % C, 68.67; % H, 8.44; % N, 14.21.

Example 282-Methyl-1-(2-methylpropyl)-7-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethoxy}-1H-imidazo[4,5-c]quinolin-4-amine

A modification of the method described in Example 19 was used to convert2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amineto 0.195 g of2-methyl-1-(2-methylpropyl)-7-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethoxy}-1H-imidazo[4,5-c]quinolin-4-amine,which was isolated an off-white powder, mp 205-208° C. The product wasnot recrystallized.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.2 Hz, 1H), 7.05 (d, J=3.1 Hz,1H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.45 (s, 2H), 4.27 (d, J=7.4 Hz, 2H),4.10 (t, J=5.5 Hz, 2H), 3.64-3.52 (m, 6H), 3.10 (at, J=4.6 Hz, 4H), 2.73(at, J=11.9 Hz, 2H), 2.56 (s, 3H), 2.21-2.12 (m, 1H), 1.77-1.65 (m, 5H),1.23-1.09 (m, 2H), 0.93 (d, J=6.6 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 163.2, 157.2, 151.8, 149.3, 146.3, 132.9,124.9, 121.2, 111.6, 108.9, 107.9, 65.9, 65.0, 51.7, 47.1, 46.4, 35.2,32.7, 31.3, 28.8, 19.3, 14.0;

MS (APCI) m/z 495.3080 (495.3084 calcd for C₂₇H₃₈N₆O₃, M+H).

Anal. Calcd. for C₂₇H₃₈N₆O₃: % C, 65.56; % H, 7.74; % N, 16.99. Found: %C, 65.21; % H, 7.40; % N, 16.68.

Example 294-(2-{[4-Amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N-cyclohexylpiperidine-1-carboxamide

A solution of2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine(0.300 g, 0.786 mmol) in chloroform was cooled to 0° C. Cyclohexylisocyanate (0.100 mL, 0.783 mmol) was added dropwise, and the reactionwas stirred for 30 minutes. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluting with dichloromethane:methanol ranging in ratios from99:1 to 95:5). The resulting product was recrystallized from ethanol toprovide 0.130 g of4-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N-cyclohexylpiperidine-1-carboxamideas a white powder, mp 213.7-215.7° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.5 Hz, 1H), 7.05 (d, J=3.0 Hz,1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.43 (s, 2H), 6.06 (d, J=7.6 Hz, 1H),4.27 (d, J=7.5 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 4.0-3.92 (m, 2H),3.44-3.3 (m, 1H), 2.60 (t, J=11.5 Hz, 2H), 2.56 (s, 3H), 2.16 (m, 1H),1.77-1.50 (m, 10H), 1.3-0.96 (m, 7H), 0.93 (d, J=6.3 Hz, 6H);

MS (APCI) m/z 507.3465 (507.3448 calcd for C₂₉H₄₂N₆O₂, M+H).

Anal. Calcd. for C₂₉H₄₂N₆O₂.0.5H₂O: % C, 67.54; % H, 8.40; % N, 16.30.Found: % C, 67.78; % H, 8.43; % N, 16.46.

Example 302-Ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

The general method described in Part A of Example 9 was followed.Triethyl orthopropionate (7.66 mL, 58.1 mmol) was added in lieu oftriethyl orthoacetate to a solution of7-benzyloxy-N⁴-(2-methylpropyl)quinoline-3,4-diamine (18.68 g, 58.11mmol) in xylenes (200 mL). At the end of the reaction, the precipitatewas collected in three crops to provide 7.16 g of7-benzyloxy-2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as alight-brown solid, mp 127° C.

Anal. Calcd. for C₂₃H₂₅N₃O: % C, 76.85; % H, 7.01; % N, 11.69. Found: %C, 76.86; % H, 7.10; % N, 11.77.

Part B

The general method described in Part J of Example 1 was followed using7-benzyloxy-2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (3.43g, 9.54 mmol) in lieu of7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.The crude product was recrystallized from acetonitrile, isolated byfiltration, and dried for two days in an oven at 60° C. to provide 0.92g of 2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol as anoff-white solid, mp>250° C.

Anal. Calcd. for C₁₆H₁₉N₃O: % C, 71.35; % H, 7.11; % N, 15.60. Found: %C, 71.36; % H, 7.02; % N, 15.60.

Part C

A solution of bromoacetyl bromide (3.0 mL, 0.034 mol) in dichloromethane(240 mL) was cooled to −25° C. A solution of morpholine (9.0 mL, 0.10mol) in dichloromethane (20 mL) was slowly added over a period of onehour. After the addition was complete, the reaction was stirred at −25°C. for 15 minutes and allowed to warm to ambient temperature.Dichloromethane was added, and the resulting solution was washed withwater, 1N aqueous hydrogen chloride, and brine; dried over magnesiumsulfate; filtered; and concentrated under reduced pressure to provide4-(2-bromoacetyl)morpholine as a colorless oil.

Part D

Under a nitrogen atmosphere, a mixture of2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.97 g, 7.31mmol), solid cesium carbonate (4.77 g, 14.6 mmol), and DMF (105 mL) washeated at 85° C. for 30 minutes. The heat was removed, and a solution of4-(2-bromoacetyl)morpholine (1.83 g, 8.77 mmol) in DMF (20 mL) was addedover a period of 12 minutes. The reaction was heated at 85° C. for 3.5hours, and methanol (1 mL) was then added. The reaction mixture wasfiltered to remove solids, and the filtrate was concentrated underreduced pressure to provide an orange oil. The oil was triturated withethyl acetate and water to provide a fluffy, white solid that wasisolated by filtration. The filtrate was concentrated under reducedpressure to provide a solid that was stirred with diethyl ether andwater and isolated by filtration. The two solids were combined and driedin a vacuum oven at 60° C. to provide 2.75 g of2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolineas a yellow semi-solid.

Part E

Over a period of 30 minutes, mCPBA (1.85 g, 5.47 mmol, 50% pure) wasadded in four portions to a solution of2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinoline(2.13 g, 5.47 mmol) in chloroform (200 mL). The reaction was stirredovernight at ambient temperature, washed twice with 1% aqueous sodiumcarbonate, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluting with 95:5dichloromethane:methanol) to provide 0.53 g of2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-1H-imidazo[4,5-c]quinoline.

Part F

Ammonium hydroxide (0.5 mL) was added to a solution of2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-1H-imidazo[4,5-c]quinoline(0.53 g, 1.28 mmol) in dichloromethane (3 mL), and the mixture wascooled to 0° C. p-Toluenesulfonyl chloride (0.29 g, 1.5 mmol) was addedin small portions over a period of 20 minutes. The reaction was stirredat ambient temperature overnight. The reaction mixture was partitionedbetween dichloromethane and 1% aqueous sodium carbonate. The organicfraction was washed with 1% aqueous sodium carbonate (2×30 mL), driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The crude product was recrystallized from ethyl acetate,isolated by filtration, washed with cold hexanes, and dried under highvacuum at 55° C. to provide 0.391 g of2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-4-amineas off-white needles, mp 219-220° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=9.0 Hz, 1H), 7.05 (d, J=2.4 Hz,1H), 6.94 (dd, J=9.0, 2.7 Hz, 1H), 6.4 (br s, 2H), 4.9 (s, 2H), 4.28 (d,J=7.2 Hz, 2H), 4.9-4.28 (m, 8H), 2.91 (q, J=7.5 Hz, 2H), 2.15 (septet,J=6.7 Hz, 1H), 1.36 (t, J=7.5 Hz, 3H), 0.91 (d, J=6.6 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 166.5, 156.9, 154.1, 152.3, 146.7, 133.2,125.5, 121.5, 111.8, 109.7, 108.9, 66.4, 66.3, 51.5, 45.2, 42.0, 29.1,20.5, 19.5, 12.4;

MS (ESI) m/z 412.2344 (412.2349 calcd. for C₂₂H₂₉N₅O₃, M+H).

Anal. Calcd. for C₂₂H₂₉N₅O₃: % C, 64.21; % H, 7.10; % N, 17.02. Found: %C, 64.07; % H, 7.21; % N, 16.99.

Example 312-Butyl-1-methyl-8-[(5-morpholin-4-yl-5-oxopentyl)oxy]-1H-imidazo[4,5-c]quinolin-4-aminetrifluoroacetate

Part A

Methylamine (available as a 40% solution in water, 24 mL, 0.28 mol) wasadded to a solution of 6-benzyloxy-4-chloro-3-nitroquinoline (15.0 g,48.5 mmol), prepared as described in Parts A-D of Example 2, indistilled water (300 mL), and the reaction was stirred at 100° C. for1.5 hours. The reaction was allowed to cool to ambient temperature andstirred for four hours. A precipitate formed, which was isolated byfiltration and washed with distilled water (3×60 mL). The solid wascombined with material from another run and recrystallized from2-propanol. The crystals were isolated by filtration, washed twice withcold hexanes, and dried for three days under high vacuum to provide24.10 g of (6-benzyloxy-3-nitroquinolin-4-yl)methylamine as yellowcrystals.

Part B

A warm solution (37° C.) of(6-benzyloxy-3-nitroquinolin-4-yl)methylamine (23.98 g, 77.6 mmol) intoluene (1.5 L) was added to a Parr vessel containing 5% platinum oncarbon (11.78 g, 0.0604 mol) and a small volume of toluene. The vesselwas placed under hydrogen pressure (35 psi, 2.4×10⁵ Pa) for 2.5 hours.The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure at 55° C. to provide 15.57 g of6-benzyloxy-N⁴-methylquinoline-3,4-diamine as a brown oil.

Part C

Under a nitrogen atmosphere, trimethyl orthovalerate (18.51 mL, 0.107mol) was added dropwise to a solution of6-benzyloxy-N⁴-methylquinoline-3,4-diamine (15.57 g, 0.0537 mol) inxylenes (150 mL), and the reaction was heated at reflux temperatureovernight. The reaction was not complete as evidenced by thin layerchromatography (TLC), and additional trimethyl orthovalerate (9.25 mL,0.0537 mol) was added. The reaction was heated at reflux overnight, anda Dean-Stark trap was used to collect the volatiles. The reaction wasthen heated at 170° C. for 4.5 hours, and about 100 mL of solvent wereremoved by distillation. The reaction mixture was allowed to cool toambient temperature; a precipitate formed over a period of three days.The mixture was diluted with hexanes, and the precipitate was isolatedby filtration and washed with hexanes to provide 15.64 g of8-benzyloxy-2-butyl-1-methyl-1H-imidazo[4,5-c]quinoline.

Part D

A modification of the general method described in Part J of Example 1was followed using8-benzyloxy-2-butyl-1-methyl-1H-imidazo[4,5-c]quinoline (14.65 g, 42.4mmol) in lieu of7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.The reaction was placed under hydrogen pressure for 3.5 hours. Thecatalyst was removed by filtration and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure to a small volume, andhexanes were added. A precipitate formed, and the mixture was storedovernight in a refrigerator. The solid was isolated by filtration,washed with hexanes (500 mL), and dried for three days under high vacuumto provide 9.40 g of 2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol asa white solid, mp 219-220.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.99 (s, 1H), 8.89 (s, 1H), 7.97 (d, J=9.0Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.21 (dd, J=9.0, 2.7 Hz, 1H), 4.13 (s,3H), 2.94 (t, J=7.6 Hz, 2H), 1.79 (quintet, J=7.6 Hz, 2H), 1.44 (sextet,J=7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H).

MS (APCI) m/e 256.2 (256.3 calcd for C₁₅H₁₇N₃O, M+H).

Anal. Calcd. for C₁₅H₁₇N₃O: % C, 70.56; % H, 6.71; % N, 16.46. Found: %C, 70.60; % H, 6.65; % N, 16.38.

Part E

Under a nitrogen atmosphere, 5-bromovaleryl chloride (4.0 mL, 30 mmol)was added dropwise to a solution of morpholine (3.13 mL, 36 mmol) andtriethylamine (6.25 mL, 45 mmol) in anhydrous THF (200 mL), and thereaction was stirred for 3.5 hours. Water (100 mL) was added, and theresulting solution was extracted with ethyl acetate (250 mL+150 mL). Thecombined extracts were washed with aqueous hydrogen chloride (100 mL of1 N), water (60 mL), and brine (100 mL); dried over magnesium sulfate;filtered; concentrated under reduced pressure; and further dried underhigh vacuum to provide 6.60 g of 4-(5-bromopentanoyl)morpholine as ayellow oil.

Part F

A modification of the general method described in Part D of Example 30was followed using 2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol (1.2g, 4.7 mmol) in lieu of2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol and4-(5-bromopentanoyl)morpholine (3.7 mmol) in lieu of4-(2-bromoacetyl)morpholine. After the reaction was heated overnight, ananalysis by TLC indicated the presence of starting material. Additional4-(5-bromopentanoyl)morpholine (2.2 g) and cesium carbonate (0.5 g) wereadded, and the reaction was heated at 80° C. overnight. After thesolution was concentrated, the residue was further dried under highvacuum overnight and then dissolved in ethyl acetate. The resultingsolution was washed with water and concentrated under reduced pressure.The solid was purified by column chromatography on silica gel (elutingwith 90:10 dichloromethane:methanol) to provide an oil, which wasstirred with diethyl ether and allowed to stand over three days in arefrigerator. A precipitate formed, which was isolated by filtration toprovide 0.770 g of2-butyl-1-methyl-8-[(5-morpholin-4-yl-5-oxopentyl)oxy]-1H-imidazo[4,5-c]quinolineas pale yellow crystals.

Part G

The general method described in Part E of Example 30 was used to convert2-butyl-1-methyl-8-[(5-morpholin-4-yl-5-oxopentyl)oxy]-1H-imidazo[4,5-c]quinoline(0.770 g, 1.81 mmol) to2-butyl-1-methyl-8-[(5-morpholin-4-yl-5-oxopentyl)oxy]-5-oxido-1H-imidazo[4,5-c]quinoline,obtained as mixture with starting material.

Part H

Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.357 mL, 2.99mmol) was added dropwise to a solution of the material from Part G inanhydrous dichloromethane (25 mL), and the reaction was stirred for sixhours at ambient temperature. The reaction was incomplete as evidencedby a TLC analysis. Additional trichloroacetyl isocyante (0.10 mL) wasadded, and the reaction was stirred for 1.5 hours. Ammonium hydroxide(four drops of 7% by weight in methanol) was added, and the volatileswere removed under reduced pressure. The resulting orange solid waspurified by column chromatography on silica gel (eluting with 90:10dichloromethane:methanol) and further purified by preparativehigh-performance liquid chromatography (prep HPLC) with fractioncollection by UV triggering. The prep HPLC fractions were analyzed usinga Micromass Platform LC/MS, and the appropriate fractions werecentrifuge evaporated. The prep HPLC separation was done by reversedphase chromatography with a Phenomenex Luna C18(2) column (10×50 mm, 5micron particle size) at a flow rate of 16 mL/min. The mobile phase wasa gradient mixture of water and acetonitrile (0.05% trifluoroacetic acidin each) from 5 to 95% acetonitrile in 6.5 minutes. The resulting solidwas dried under vacuum for several days to provide2-butyl-1-methyl-8-[(5-morpholin-4-yl-5-oxopentyl)oxy]-1H-imidazo[4,5-c]quinolinetrifluoroacetate as a beige powder, mp 155.5-156.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (br s, 2H), 7.76 (d, J=9.3 Hz, 1H),7.71 (d, J=2.7 Hz, 1H), 7.38 (dd, J=9.3, 2.4 Hz, 1H), 4.2-4.15 (m, 5H),3.6-3.52 (m, 4H), 3.5-3.4 (m, 4H), 3.0 (t, J=7.8 Hz, 2H), 2.41 (t, J=7.2Hz, 2H), 1.85-1.62 (m, 6H), 1.44 (sextet, J=7.2 Hz, 2H), 0.96 (t, J=7.5Hz, 3H),

¹³C NMR (150 MHz, DMSO-d₆) δ 171.5, 157.3, 156.2, 148.7, 136.1, 128.8,125.0, 120.4, 119.2, 114.6, 105.1, 68.7, 67.0, 46.2, 43.6, 42.2, 34.3,32.5, 29.9, 29.1, 27.1, 22.6, 22.2, 14.5; MS (ESI) m/z 440.2676 (Calcd.for C₂₄H₃₃N₅O₃ 440.2662, M+H);

Anal. Calcd. for C₂₄H₃₃N₅O₃.1.5 C₂HF₃O₂.0.62 H₂O: % C, 52.11; % H, 5.80;% N, 11.25; % F, 13.74. Found: % C, 51.93; % H, 5.61; % N, 11.31; % F,12.45.

Examples 32-36 Part A

The general methods described in Parts C-E of Example 30 were followed.According to the method of Part C the amine listed in the table belowwas used to prepare the bromo reagent listed in the table below.According to the method of Part D,2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol was treated with thebromo reagent, and the product was oxidized according to the method ofPart E. For Example 35, the crude product isolated after Part D wasrecrystallized from water. Chromatographic purification as described inPart E was carried out only for Example 36; the remaining N-oxides wereused without purification.

Part B

Under a nitrogen atmosphere, trichloroacetyl isocyanate (1.5equivalents) was added dropwise to a solution of the material from PartA in anhydrous dichloromethane, and the reaction was stirred for betweentwo and five hours. The solvent was removed under reduced pressure. Theresidue was diluted with methanol, and a solution of sodium methoxide (5equivalents, 25% in methanol) was slowly added. The reaction was stirredovernight, and a precipitate formed. The precipitate was isolated byfiltration, washed with three times with cold hexanes. The purificationand characterization of the final compounds are described for eachexample below the table.

Example Amine Bromo Reagent R 32 Morpholine 4-(2-Bromoacetyl) morpholine

33 Piperidine 2-Bromo-1-piperidin-1- ylethanone

34 Benzylmethylamine N-Benzyl-2-bromo-N- methylacetamide

35 Diethylamine N,N-Diethyl-2- bromoacetamide

36 Bis(methoxyethylamine) 2-Bromo-N,N-bis-(2- methoxyethyl)acetamide

Example 322-Butyl-1-methyl-8-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

The crude product was recrystallized from methyl acetate to provide2-butyl-1-methyl-8-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 256.8-257.2° C.

¹H NMR (500 MHz, DMSO-d₆) δ 7.61 (d, J=3.0 Hz, 1H), 7.54 (d, J=9.0 Hz,1H), 7.12 (dd, J=9.0, 2.5 Hz, 1H), 6.24-6.19 (br s, 2H), 4.94 (s, 2H),4.10 (s, 3H), 3.65-3.45 (m, 8H), 2.93 (t, J=7.5 Hz, 2H), 1.75 (pentet,J=7.5 Hz, 2H), 1.43 (sextet, J=7.5 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H);

MS (APCI) m/z 398 (M+H)⁺,

Anal. Calcd. for C₂₁H₂₇N₅O₃: % C, 63.46; % H, 6.85; % N, 17.62. Found: %C, 63.39; % H, 6.86; % N, 17.75.

Example 332-Butyl-1-methyl-8-(2-oxo-2-piperidin-1-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

The crude product was recrystallized from methyl acetate and dried forfour hours in a vacuum oven at 45° C. to provide2-butyl-1-methyl-8-(2-oxo-2-piperidin-1-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 222.5-223.4° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (d, J=2.7 Hz, 1H), 7.53 (d, J=9.0 Hz,1H), 7.11 (dd, J=9.0, 2.7 Hz, 1H), 6.23 (br s, 2H), 4.89 (s, 2H), 4.1(s, 3H), 3.46 (br s, 4H), 2.92 (t, J=8.1 Hz, 2H), 1.75 (pentet, J=7.5Hz, 2H), 1.59-1.36 (m, 8H), 0.95 (t, J=7.2 Hz, 3H);

MS (EI) m/z 395.2327 (Calcd. for C₂₂H₂₉N₅O₂ 395.2321).

Anal. Calcd. for C₂₆H₂₉N₅O₂: % C, 66.81; % H, 7.39; % N, 17.71. Found: %C, 66.81; % H, 7.18; % N, 17.63.

Example 342-[(4-Amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-N-benzyl-N-methylacetamide

The crude product was recrystallized from a mixture of DMF and water toprovide2-[(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-N-benzyl-N-methylacetamideas an off-white solid, mp 167.4-168.8° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.64 (d, J=2.7 Hz, 1H), 7.55 (d, J=9.0 Hz,1H), 7.21 (br s, 5H), 7.10 (d, J=8.1 Hz, 1H), 5.89 (br s, 2H), 4.94 (s,2H), 4.57 (br s, 2H), 4.03 (s, 3H), 3.01 (s, 3H), 2.91 (t, J=7.2 Hz,2H), 1.78 (pentet, J=7.5 Hz, 2H), 1.45 (sextet, J=7.2 Hz, 2H), 0.95 (t,J=7.5 Hz, 3H);

MS (APCI) m/z 432 (M+H)⁺,

Anal. Calcd. for C₂₅H₂₉N₅O₂: % C, 69.58; % H, 6.77; % N, 16.23. Found: %C, 69.35; % H, 6.47; % N, 16.13.

Example 352-[(4-Amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-N,N-diethylacetamide

The crude product was purified by column chromatography on silica gel(eluting with 95:5 dichloromethane:methanol). The pure fractions wereconcentrated under reduced pressure to a small volume, and hexanes wereadded. A precipitate formed and was washed with hexanes to provide2-[(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-N,N-diethylacetamideas a white solid, mp 185.90-188.10° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (d, J=2.6 Hz, 1H), 7.54 (d, J=9.1 Hz,1H), 6.37 (dd, J=9.1, 2.7 Hz, 1H), 6.19 (s, 2H), 4.88 (s, 2H), 4.09 (s,3H), 3.41 (m, 2H), 2.92 (t, J=7.6 Hz, 2H), 1.75 (m, 2H), 1.43 (m, 2H),1.17 (t, J=7.0 Hz, 3H), 1.06 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H);

MS (EI) m/z 383.2326 (Calcd. for C₂₁H₂₉N₅O₂ 383.2321).

Anal. Calcd. for C₂₁H₂₉N₅O₂.0.15H₂O: % C, 65.31; % H, 7.65; % N, 18.13.Found: % C, 65.18; % H, 7.28; % N, 18.11.

Example 362-[(4-Amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-N,N-bis(2-methoxyethyl)acetamide

The product from the reaction with sodium methoxide did not precipitatefrom the reaction solution. The solvent was removed under reducedpressure, and the residue was recrystallized from 2-propanol, isolatedby filtration, washed with hexanes, stirred with water for two hours,isolated by filtration, and washed with water. The solid was thenrecrystallized twice from methanol, purified by column chromatography onsilica gel (eluting with 95:5 dichloromethane:methanol), andrecrystallized from dimethyl sulfoxide to provide2-[(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-N,N-bis(2-methoxyethyl)acetamideas a peach-colored, crystalline solid, mp 125-128° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.57 (d, J=3.0 Hz, 1H), 7.53 (d, J=9.3 Hz,1H), 7.08 (dd, J=9.3, 3.0 Hz, 1H), 6.17 (s, 2H), 4.95 (s, 2H), 4.09 (s,3H), 3.61 (t, J=4.8 Hz, 2H), 3.53 (t, J=4.8 Hz, 2H), 3.49 (t, J=5.1 Hz,2H), 3.41 (t, J=4.8 Hz, 2H), 3.41 (s, 6H), 2.93 (t, J=7.2 Hz, 2H), 1.75(pentet, J=7.8 Hz, 2H), 1.43 (sextet, J=7.8 Hz, 2H), 0.94 (t, J=7.8 Hz,3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 167.6, 152.8, 152.0, 149.8, 139.2, 132.5,126.7, 126.0, 115.7, 114.7, 102.5, 69.8, 69.2, 66.0, 57.9, 57.5, 46.5,44.6, 32.4, 29.0, 25.8, 21.4, 13.3;

MS (EI) m/z 443.2529 (443.2533 calcd. for C₂₃H₃₃N₅O₄).

Example 37 tert-Butyl4-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-1-carboxylate

Part A

The method described in Part L of Example 2 was used to treat2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol with tert-butyl4-(2-iodoethyl)piperidine-1-carboxylate. Following chromatographicpurification, tert-butyl4-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-1-carboxylatewas isolated as a viscous, pale yellow oil containing some DMF.

¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 7.74(d, J=3.0 Hz, 1H), 7.29 (dd, J=9.2, 2.6 Hz, 1H), 4.51-4.42 (m, 1H), 4.19(s, 3H), 4.16 (t, J=7.2 Hz, 2H), 3.95-3.84 (m, 1H), 2.98 (t, J=5.4 Hz,2H), 2.29-2.16 (m, 1H), 2.03-1.87 (m, 1H), 1.80 (quintet, J=7.7 Hz, 2H),1.70-1.37 (m, 9H), 1.29 (s, 9H), 0.95 (t, J=7.7 Hz, 3H).

Part B

The methods described in Parts M and N of Example 2 were used to converttert-butyl4-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-1-carboxylateto tert-butyl4-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-1-carboxylate,which was obtained as an off-white powder, mp 171.1-173.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=3.1 Hz, 1H), 7.53 (d, J=8.6 Hz,1H), 7.06 (dd, J=9.3, 2.9 Hz, 1H), 6.19 (s, 2H), 4.49-4.40 (m, 1H), 4.10(s, 3H), 4.04 (t, J=6.0 Hz, 2H), 3.94-3.81 (m, 1H), 2.92 (t, J=7.9 Hz,2H), 2.9-2.75 (m, 1H), 2.24-2.1 (m, 1H), 1.96-1.84 (m, 1H), 1.75(quintet, J=7.7 Hz, 2H), 1.68-1.50 (m, 5H), 1.43 (sextet, J=7.5 Hz, 2H),1.31 (s, 9H), 1.31-1.2 (m, 1H), 0.95 (t, J=7.2 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 154.0, 153.1, 152.9, 150.1, 139.5, 133.0,127.3, 126.5, 116.2, 115.3, 102.2, 78.3, 65.2, 47.4, 32.9, 29.5, 29.1,28.4, 28.0, 26.2, 25.3, 21.9, 18.6, 13.7; MS (APCI) m/z 482.3111(482.3131 calcd for C₂₇H₃₉N₅O₃, M+H).

Anal. Calcd. for C₂₇H₃₉N₅O₃: % C, 67.33; % H, 8.16; % N, 14.54. Found: %C, 67.37; % H, 8.22; % N, 14.48.

Example 382-Butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

A modification of the method described in Part O of Example 2 was usedto deprotect tert-butyl4-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-1-carboxylate.The crude product was triturated with diethyl ether and isolated byfiltration to provide2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amineas a yellow powder, mp 210-212° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.58 (d, J=2.6 Hz, 1H), 7.52 (d, J=9.4 Hz,1H), 7.08 (dd, J=9.2, 2.8 Hz, 1H), 6.16 (s, 2H), 4.16 (at, J=6.2 Hz,2H), 4.12 (s, 3H), 2.96-2.87 (m, 1H), 2.92 (at, J=7.9 Hz, 2H), 2.68-2.56(m, 1H), 2.56-2.43 (m, 1H), 2.12-1.96 (m, 1H), 1.75 (quintet, J=7.0 Hz,2H), 1.69-1.60 (m, 4H), 1.51-1.24 (m, 5H), 1.03-0.97 (m, 1H), 0.95 (t,J=7.6 Hz, 3H);

MS (APCI) m/z 382.2621 (382.2607 calcd for C₂₂H₃₁N₅O, M+H).

Anal. Calcd. for C₂₂H₃₁N₅O: % C, 69.26; % H, 8.19; % N, 18.36. Found: %C, 68.87; % H, 8.13; % N, 18.12.

Example 391-{4-[2-(4-Amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidin-1-yl}-2-methylpropan-1-one

A modification of the method described in Example 15 was followed. Thereaction solvent was 1-methylpyrrolidin-2-one, and2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-aminewas used as the starting material. Following recrystallization fromacetonitrile,1-{4-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidin-1-yl}-2-methylpropan-1-onewas isolated as yellow needles, mp 189.4-192.6° C.

MS (APCI) m/z 452.3031 (452.3026 calcd for C₂₆H₃₇N₅O₂, M+H).

Anal. Calcd. for C₂₆H₃₇N₅O₂.0.60H₂O: % C, 67.53; % H, 8.33; % N, 15.14.Found: % C, 67.59; % H, 8.23; % N, 15.39.

Example 402-Butyl-8-{2-[1-(cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine

A modification of the method described in Example 15 was used to treat2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-aminewith cyclopentanecarbonyl chloride. The crude product was purified bycolumn chromatography on silica gel to provide2-butyl-8-{2-[1-(cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-1-methyl-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 147.2-150.1° C.

MS (APCI) m/z 478.3173 (478.3182 calcd for C₂₄H₃₉N₅O₂, M+H).

Anal. Calcd. for C₂₄H₃₉N₅O₂.0.45H₂O: % C, 69.23; % H, 8.28; % N, 14.42.Found: % C, 68.91; % H, 8.20; % N, 14.31.

Example 412-Butyl-8-{2-[1-(methanesulfonyl)piperidin-4-yl]ethoxy}-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine

A suspension of2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine(0.320 g, 0.839 mmol) and methanesulfonic anhydride (0.153, 0.878 mmol)in dichloromethane (20 mL) was stirred for five minutes. Triethylamine(0.122 mL, 0.875 mmol) was added dropwise, and the solution was stirredfor 1.5 hours. The reaction was poured into water, and the organic layerwas separated and stirred with 10% aqueous sodium hydroxide for 20minutes. The organic layer was separated and washed with brine, driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The resulting solid was recrystallized from acetonitrile toyield 0.174 g of2-butyl-8-{2-[1-(methanesulfonyl)piperidin-4-yl]ethoxy}-1-methyl-1H-imidazo[4,5-c]quinolin-4-amineas a feathery, white solid, mp 198-199.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.60 (d, J=2.7 Hz, 1H), 7.53 (d, J=9.1 Hz,1H), 7.09 (dd, J=9.1, 2.7 Hz, 1H), 6.16 (s, 2H), 4.20-4.16 (m, 3H), 4.10(s, 3H), 3.65-3.56 (m, 1H), 3.11-3.01 (m, 1H), 2.98-2.90 (m, 2H), 2.93(s, 3H), 2.28-2.16 (m, 1H), 1.98 (sextet, J=6.8 Hz, 1H), 1.80-1.36 (m,10H), 0.95 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 153.1, 152.8, 150.1, 139.5, 133.0, 127.3,126.4, 116.4, 115.3, 102.7, 65.4, 49.3, 32.9, 29.5, 28.9, 27.8, 26.2,24.7, 21.8, 18.2, 13.7;

MS (APCI) m/z 460.2396 (460.2382 calcd for C₂₃H₃₃N₅O₃S, M+H).

Anal. Calcd. for C₂₃H₃₃N₅O₃S: % C, 60.11; % H, 7.24; % N, 15.24; % S,6.98. Found: % C, 59.95; % H, 7.21; % N, 15.30; % S, 6.92.

Example 422-Butyl-1-methyl-8-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethoxy}-1H-imidazo[4,5-c]quinolin-4-amine

A modification of the method described in Example 19 was followed. Thereaction solvent was 1-methylpyrrolidin-2-one, and2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-aminewas used as the starting material. The reaction mixture was poured intowater, and a precipitate formed. The precipitate was isolated byfiltration, washed with water, and dried for two days in a vacuum ovenat 70° C. to provide 0.320 g of2-butyl-1-methyl-8-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethoxy}-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 152.8° C. (decomposition).

¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=3.2 Hz, 1H), 7.53 (d, J=9.3 Hz,1H), 7.06 (dd, J=9.2, 2.8 Hz, 1H), 6.17 (s, 2H), 4.19-3.96 (m, 3H), 4.11(s, 3H), 3.54-3.34 (m, 5H), 3.14-2.90 (m, 7H), 2.26-2.09 (m, 1H),2.04-1.89 (m, 1H), 1.75 (quintet, J=7.5 Hz, 2H), 1.68-1.51 (m, 5H), 1.43(sextet, J=7.4 Hz, 2H), 1.46-1.28 (m, 1H), 0.95 (t, J=7.5 Hz, 3H);

MS (APCI) m/z 495.3080 (495.3084 calcd for C₂₇H₃₈N₆O₃, M+H).

Anal. Calcd. for C₂₇H₃₈N₆O₃: % C, 65.56; % H, 7.74; % N, 16.99. Found: %C, 65.33; % H, 7.88; % N, 16.95.

Example 43N-[2-(4-Amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]propanamide

Part A

A mixture of 2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol (0.51 g,2.0 mmol), prepared as described in Parts A-D of Example 31, and2-ethyl-2-oxazoline (0.5 g, 5 mmol) were heated at 150° C. for fourhours. Additional 2-ethyl-2-oxazoline (2 mL, 2 mmol) was added, and theheating was continued for a total of four days. The reaction wasdissolved in dichloromethane, and the resulting solution was washed withaqueous potassium hydroxide (20 mL of 4 N), dried over magnesiumsulfate, and concentrated under reduced pressure. The crude product wasrecrystallized from methyl acetate (20 mL) to provide 0.20 g ofN-{2-[2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethyl}propanamide.

Part B

The general method described in Part E of Example 30 was used to convertN-{2-[2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethyl}propanamide(0.18 g, 0.51 mmol) to 0.14 g ofN-{2-[2-butyl-1-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethyl}propanamide.The reaction was complete in two hours.

Part C

Ammonium hydroxide (5 mL) and p-toluenesulfonyl chloride (0.072 g, 0.38mmol) were added with rapid stirring to a solution ofN-{2-[2-butyl-1-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethyl}propanamide(0.14 g, 0.38 mmol) in dichloromethane (15 mL), and the mixture wasstirred at ambient temperature for one hour. A precipitate formed andwas isolated by filtration, washed with water, and dried under reducedpressure to provideN-[2-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]propanamideas a solid, mp 250-255° C. (decomposition).

Example 442-[(4-Amino-1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetic acid

Part A

7-Benzyloxy-1,2-dimethyl-1H-imidazo[4,5-c]quinoline was preparedaccording to the methods described in Parts A-C of Example 31. In PartC, triethyl orthoformate was used in lieu of trimethyl orthovalerate. Asolution of 7-benzyloxy-1,2-dimethyl-1H-imidazo[4,5-c]quinoline inethanol was added to a Parr vessel with 10% palladium on carbon. Thereaction was placed under hydrogen pressure (35 psi, 2.4×10⁵ Pa) for 20hours. The reaction mixture was then filtered through a layer of CELITEfilter aid, and the filtrate was concentrated under reduced pressure.The residue was dissolved in acetic acid with heating, and the hotsolution was filtered and concentrated under reduced pressure. Theresulting beige solid was dissolved in 1 N aqueous hydrochloric acid,and deactivated carbon was added. The solution was heated, filtered, andtreated with 50% aqueous sodium hydroxide. A precipitate formed and wasisolated by filtration to provide1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-ol as a solid, mp>300° C.

Part B

Sodium hydride (0.61 g, 15 mmol, available as a 60% dispersion inmineral oil) was added to a solution of1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-ol (2.5 g, 12 mmol) in DMF. Thereaction mixture was stirred for 30 minutes, and ethyl bromoacetate(1.96 g, 11.7 mmol) was added. The stirring was continued for fivehours, and a small volume of ethanol was added. The volatiles wereremoved under reduced pressure, and the residue was dissolved indichloromethane. The resulting solution was washed three times withdeionized water, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting yellow solid wasrecrystallized from ethyl acetate to provide 1.65 g of ethyl2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate as a whitesolid.

Part C

Ethyl 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate (1.6g, 5.35 mmol) was added to a solution of potassium hydroxide (0.90 g,0.16 mol) in a 50:50 mixture of methanol:water (30 mL). The solution wasstirred under a nitrogen atmosphere until it was complete as evidencedby HPLC analysis. The methanol was removed under reduced pressure, and 6N aqueous hydrochloric acid was added until the solution exhibited aneutral pH. A precipitate formed and was isolated by filtration toprovide 1.25 g of2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetic acid as awhite solid, mp 290° C. (decomposition).

Part D

Morpholine (0.39 g, 4.4 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.85 g,4.4 mmol) were added to a solution of2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetic acid (1.20 g,4.42 mmol) in pyridine, and the reaction was stirred for four days undera nitrogen atmosphere. The solvent was removed under reduced pressure,and the residue was stirred with heptane, which was then removed underreduced pressure. The resulting orange solid was purified by columnchromatography on silica gel (eluting with 90:10dichloromethane:methanol) to provide2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-1-morpholin-1-ylethanoneas a pale yellow solid.

Part E

The general method described in Part E of Example 30 was followed using2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-1-morpholin-1-ylethanone(0.97 g, 2.85 mmol) as the starting material. The reaction was completein two hours. The product was soluble in aqueous sodium carbonate;therefore, the aqueous washings were concentrated under reducedpressure. 2-Propanol was added to the residue with heating, and themixture was filtered. The filtrate was concentrated under reducedpressure to provide 0.14 g of2-[(1,2-dimethyl-5-oxido-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-1-morpholin-1-ylethanone.

Part F

Ammonium hydroxide (30 mL) and p-toluenesulfonyl chloride (0.46 g, 2.4mmol) were added with rapid stirring to a solution of2-[(1,2-dimethyl-5-oxido-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-1-morpholin-1-ylethanone(0.86 g, 2.4 mmol) in dichloromethane, and the mixture was stirred atambient temperature for two days. The volatiles were removed underreduced pressure, and the residue was recrystallized from 2-propanol toprovide2-[(4-amino-1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]-1-morpholin-1-ylethanonep-toluenesulfonate as a white solid.

Part G

Claisen Reagent, prepared from potassium hydroxide (35 g), water (25mL), and methanol (100 mL), was added to the material from Part F, andthe mixture was stirred for one hour. Hydrochloric acid (6 N) was addeduntil the pH of the reaction mixture was neutral. A precipitate formedand was isolated by filtration to provide 0.01 g of2-[(4-amino-1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetic acidas an orange solid, mp 298° C. (decomposition).

Example 45N-(2-{4-Amino-2-ethoxymethyl-7-[6-(methanesulfonylamino)hexyloxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)methanesulfonamide

Part A

7-Benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol), prepared asdescribed in Parts A-D of Example 1, was treated according to thegeneral method described in Part E of Example 1.1,2-Diamino-2-methylpropane (5.29 mL, 50.6 mmol) was used in lieu ofisobutylamine. After the work-up, the crude product was passed through alayer of silica gel (eluting sequentially with chloroform and 96:4chloroform:methanol) to provide 12.4 g of(2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as ayellow solid.

Part B

Under a nitrogen atmosphere, a solution of(2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (12.4 g,33.9 mmol) in dichloromethane (400 mL) was cooled to 0° C. Triethylamine(9.43 mL, 67.8 mmol) and methanesulfonic anhydride (5.90 g, 33.9 mmol)were sequentially added, and the reaction was stirred at ambienttemperature for two hours. An analysis by HPLC indicated that thereaction was incomplete, and additional methanesulfonic anhydride (1.4g, 8.0 mmol) was added. The reaction was stirred for an additional 90minutes, and additional methanesulfonic anhydride (0.7 g, 4 mmol) wasadded. The reaction was stirred for an additional three hours, andsaturated aqueous sodium bicarbonate (200 mL) was added. A precipitatebegan to form in the organic layer, which was separated and concentratedunder reduced pressure to provide a yellow solid. The solid wastriturated with water (200 mL) with heating, isolated by filtration,washed with water (3×100 mL) and diethyl ether (3×50 mL), and driedovernight under vacuum to provide 14.8 g ofN-[1,1-dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]methanesulfonamideas a yellow powder.

Part C

N-[1,1-Dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]methanesulfonamide(14.8 g, 33.3 mmol) was mixed with acetonitrile (300 mL) and added to aParr flask; 5% platinum on carbon (2 g) was added. The reaction wasflushed with nitrogen and placed under hydrogen pressure (40 psi,2.8×10⁵ Pa) for 5.5 hours with the hydrogen replaced after two hours. Ananalysis by TLC indicated the presence of starting material. Additionalacetonitrile (200 mL) and 5% platinum on carbon (2 g) were added, andthe reaction was placed under hydrogen pressure overnight. The reactionmixture was filtered through a layer of CELITE filter aid, and thefilter cake was washed with acetonitrile. The filtrate was concentratedunder reduced pressure. Toluene and dichloromethane were added andremoved under reduced pressure twice to yield 12.6 g ofN-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamideas a solid.

Part D

Under a nitrogen atmosphere, a solution ofN-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide(12.6 g, 30.4 mmol) in dichloromethane (300 mL) was cooled to ˜0° C.;triethylamine (4.23 mL, 30.4 mmol) was added. Ethoxy acetyl chloride(3.33 mL, 30.4 mmol) was added dropwise, and the reaction was stirred atambient temperature for 1.5 hours. The volatiles were removed underreduced pressure, and the residue was dissolved in ethanol (300 mL).Triethylamine (13 mL) was added, and the reaction was heated at refluxovernight and allowed to cool to ambient temperature. The volatiles wereremoved under reduced pressure. The residue was dissolved indichloromethane (300 mL), and the resulting solution was washed withwater (2×100 mL) and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide a brown oil. The oil waspurified by column chromatography on silica gel (eluting with 97.5:2.5chloroform:methanol) to provide 12.4 g ofN-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamideas a beige solid.

Part E

A solution ofN-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide(9.38 g, 19.5 mmol) in ethanol (150 mL) was added to a Parr vesselcontaining 10% palladium on carbon (0.83 g). The reaction was placedunder hydrogen pressure (50 psi, 3.4×10⁵ Pa) over two nights. Startingmaterial remained as evidenced by a TLC analysis, and additional 10%palladium on carbon (1.02 g) was added. The reaction was continued foran additional eight hours. The reaction mixture was filtered through alayer of CELITE filter aid, and the filter cake was washed with ethanoland methanol. The filtrate was concentrated under reduced pressure, andthe residue was several times dissolved in toluene and concentratedunder reduced pressure to yield a yellow powder, which was dried underhigh vacuum to provide 7.37 g ofN-[2-(2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamideas a yellow solid.

Part F

The methods described in Parts J and K of Example 2 were followed using6-amino-1-hexanol (62 g, 0.53 mmol) in lieu of 2-aminoethanol to providetert-butyl 6-iodohexylcarbamate as a light-yellow oil.

Part G

The general method described in Part L of Example 2 was followed.N-[2-(2-Ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (7.37 g, 18.8mmol) was treated with tert-butyl 6-iodohexylcarbamate (6.75 g, 20.6mmol). The crude product was purified by column chromatography on silicagel (eluting sequentially with 95:5 and 92.5:7.5dichloromethane:methanol) to provide 8.5 g of tert-butyl{6-[2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-1-yloxy]hexyl}carbamateas a white solid.

Part H

A modification of the method described in Part M of Example 2 was usedto convert tert-butyl{6-[2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-1-yloxy]hexyl}carbamate(8.5 g, 14.4 mmol) to tert-butyl{6-[2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yloxy]hexyl}carbamate,which was obtained as a orange solid. The reaction was complete in twohours, and the product was used without purification.

Part I

Ammonium hydroxide (20 mL) and p-toluenesulfonyl chloride (2.74 g, 14.4mmol) were added sequentially with rapid stirring to a mixture of thematerial from Part H in dichloromethane (150 mL), and the reaction wasstirred for two hours. The organic layer was then washed with saturatedaqueous sodium bicarbonate (2×) and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide tert-butyl{6-[4-amino-2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-1-yloxy]hexyl}carbamateas a red solid.

Part J

A modification of the method described in Part O of Example 2 was usedto deprotect tert-butyl{6-[4-amino-2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-1-yloxy]hexyl}carbamatewith hydrochloric acid in ethanol (50 mL of 4.25 M). Following thetreatment of the crude product with ammonium hydroxide and the remainderof the work-up procedure, 6.86 g ofN-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamidewere obtained as a tan solid and used without further purification.

Part K

A suspension ofN-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide(1.50 g, 2.96 mmol) in dichloromethane (50 mL) was cooled to 0° C.;triethylamine (825 μL, 5.92 mmol) and methanesulfonic anhydride (0.67 g,3.85 mmol) were sequentially added. The reaction was stirred at 0° C.for 30 minutes, allowed to warm to room temperature, and stirred forfour hours. The reaction solution was washed with saturated aqueoussodium bicarbonate (2×) and brine, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluting with 90:10dichloromethane:methanol) and recrystallization from dichloroethane. Thecrystals were partitioned between dichloromethane and saturated aqueoussodium bicarbonate, and the aqueous layer was extracted withdichloromethane. The combined organic fractions were washed with brine,dried over sodium sulfate, filtered, concentrated under reducedpressure, and further dried for two days under high vacuum at 60° C. toprovide 0.39 g ofN-(2-{4-amino-2-ethoxymethyl-7-[6-(methanesulfonylamino)hexyloxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)methanesulfonamideas an off-white solid, mp 176-180° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=9.4 Hz, 1H), 7.27 (s, 1H), 7.03(d, J=2.5 Hz, 1H), 6.93 (m, 1H), 6.84 (dd, J=8.7, 2.5 Hz, 1H), 6.53 (s,2H), 4.81 (s, 4H), 4.04 (t, J=6.2 Hz, 2H), 3.53 (m, 2H), 2.99 (s, 3H),2.94 (m, 2H), 2.87 (s, 3H), 1.76 (m, 2H), 1.50-1.27 (m, 12H), 1.14 (m,3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.9, 152.6, 150.0, 147.7, 134.9, 125.4,122.6, 111.4, 109.5, 108.4, 67.5, 65.7, 65.1, 57.7, 54.6, 44.7, 42.8,29.7, 29.0, 26.3, 25.8, 25.6, 15.3;

MS (APCI) m/z 585 (M+H)⁺;

Anal. Calcd. for C₂₅H₄₀N₆O₆S₂.0.30 H₂O: % C, 50.88; % H, 6.94; % N,14.24. Found: % C, 50.85; % H, 6.83; % N, 14.10.

Example 46N-(6-{[4-Amino-2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide

A modification of the method described in Park K of Example 45 wasfollowed using acetyl chloride (0.23 mL, 3.26 mmol) in lieu ofmethanesulfonic anhydride. A precipitate was present at the end of thereaction and was isolated by filtration, stirred with water for 30minutes, and isolated by filtration. The remaining reaction solution wassubjected to the aqueous work-up procedure. The two solids were combinedand purified by column chromatography on silica gel (elutingsequentially with 90:10 and 85:15 dichloromethane:methanol) to provide0.51 g ofN-(6-{[4-amino-2-ethoxymethyl-1-(2-methanesulfonylamino-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamideas an off-white powder, mp 169-171° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=9.4 Hz, 1H), 7.79 (m, 1H), 7.28(s, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.7, 2.5 Hz, 1H), 6.56 (s,2H), 4.82 (s, 4H), 4.04 (m, 2H), 3.54 (q, J=6.9 Hz, 2H), 3.02 (m, 2H),2.99 (s, 3H), 1.79 (s, 3H), 1.75 (m, 2H), 1.45-1.28 (m, 12H), 1.14 (m,3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 169.2, 157.9, 152.6, 150.0, 147.6, 134.9,125.4, 122.6, 111.4, 109.5, 108.4, 67.6, 65.7, 65.1, 57.7, 54.6, 44.7,38.8, 29.5, 29.0, 26.6, 25.8, 25.7, 22.9, 15.3;

MS (APCI) m/z 549 (M+H)⁺;

Anal. Calcd. for C₂₆H₄₀N₆O₅S: % C, 56.91; % H, 7.35; % N, 15.32. Found:% C, 56.70; % H, 7.49; % N, 15.26.

Example 47N-(4-{4-Amino-7-[6-(methanesulfonylamino)hexyloxy]-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl}butyl)methanesulfonamide

Part A

Under a nitrogen atmosphere, a solution of tert-butylN-(4-aminobutyl)carbamate (13.8 g, 73.4 mmol) and triethylamine (15.3mL, 110 mmol) was cooled to 0° C. Methanesulfonyl chloride (6.3 mL, 81mmol) was added, and the reaction was allowed to warm to ambienttemperature and stirred overnight. Aqueous acetic acid (200 mL of 10%)was added. The organic layer was then separated and washed with water(200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL),and brine; dried over sodium sulfate, filtered, and concentrated underreduced pressure to provide 18.9 g of tert-butyl[4-(methanesulfonylamino)butyl]carbamate as an off-white solid.

Part B

A solution of hydrochloric acid in ethanol was added to a solution oftert-butyl [4-(methanesulfonylamino)butyl]carbamate (18.9 g, 71.1 mmol)in ethanol (100 mL), and the reaction was heated at 100° C. for twohours. The solvent was removed under reduced pressure. A mixture ofdichloromethane:hexanes was added to the resulting oil and removed underreduced pressure; this process was repeated several times. The residuewas dried for three days under vacuum to provide 14.3 g ofN-(4-aminobutyl)methanesulfonamide hydrochloride as a tan solid.

Part C

A modification of the method described in Part E of Example 1 was usedto treat 7-benzyloxy-4-chloro-3-nitroquinoline (14.4 g, 45.8 mmol) withN-(4-aminobutyl)methanesulfonamide hydrochloride (10.2 g, 50.4 mmol) andtriethylamine (19.2 mL, 137 mmol). The reaction mixture was concentratedunder reduced pressure, and the residue was triturated with water whileheating at reflux. The resulting solid was isolated by filtration,washed with water and diethyl ether (2×100 mL), and dried under highvacuum to provide 16.8 g ofN-[4-(3-nitro-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide asa yellow powder.

Part D

The method described in Part C of Example 45 was used to convertN-[4-(3-nitro-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide(16.8 g, 37.8 mmol) to 15.1 g ofN-[4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide,which was obtained as a dark yellow solid.

Part E

The method described in Part D of Example 45 was used to treatN-[4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide(15.1 g, 36.5 mmol) with butyryl chloride (4.77 mL, 46.2 mmol). Thecrude product was purified by column chromatography on silica gel(eluting with 96:4 chloroform:methanol containing ammonium hydroxide) toprovide 11.8 g ofN-[4-(7-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas a tan solid.

Part F

The method described in Part E of Example 45 was used to convertN-[4-(7-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide(7.60 g, 16.3 mmol) to 5.75 g ofN-[4-(7-hydroxy-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide,which was obtained as a light-yellow solid.

Part G

The general method described in Part L of Example 2 was followed.N-[4-(7-hydroxy-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide(5.75 g, 15.3 mmol) was treated with tert-butyl 6-iodohexylcarbamate(5.50 g, 16.8 mmol). The crude product was purified by columnchromatography on silica gel (eluting sequentially with 95:5 and92.5:7.5 dichloromethane:methanol) to provide 6.19 g of tert-butyl(6-{1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-1-yloxy}hexyl)carbamateas a yellow solid.

Part H

A modification of the method described in Part M of Example 2 was usedto convert tert-butyl(6-{1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-1-yloxy}hexyl)carbamate(2.51 g, 4.36 mmol) to 2.54 g of tert-butyl(6-{1-[4-(methanesulfonylamino)butyl]-5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yloxy}hexyl)carbamate,which was obtained as a yellow solid. The reaction was allowed to runovernight, and the product was used without purification.

Part I

The method described in Part I of Example 45 was used to converttert-butyl(6-{1-[4-(methanesulfonylamino)butyl]-5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yloxy}hexyl)carbamate(2.54 g, 4.29 mmol) to 2.51 g of tert-butyl(6-{4-amino-1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-1-yloxy}hexyl)carbamate,obtained as a tan solid.

Part J

The method described in Part J of Example 45 was used to deprotecttert-butyl(6-{4-amino-1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-1-yloxy}hexyl)carbamate(2.51 g, 4.25 mmol). The crude product was recrystallized fromacetonitrile to provide 0.75 g ofN-{4-[4-amino-7-(6-aminohexyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamideas a tan solid. The mother liquor was concentrated under reducedpressure, and the residue was recrystallized from dichloroethane toprovide 0.48 g ofN-{4-[4-amino-7-(6-aminohexyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamideas a brown powder.

Part K

A modification of the method described in Part K of Example 45 wasfollowed usingN-{4-[4-amino-7-(6-aminohexyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide(0.86 g, 1.8 mmol) as the starting material. Methanesulfonic anhydride(470 mg, 2.7 mmol) was added over a period of 24 hours. The crudeproduct was purified by column chromatography on silica gel (elutingsequentially with 90:10 and 85:15 dichloromethane:methanol),recrystallization from ethyl acetate, and a second recrystallizationfrom 2-propanol to provide 0.38 g ofN-(4-{4-amino-7-[6-(methanesulfonylamino)hexyloxy]-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl}butyl)methanesulfonamideas a white powder, mp 138-140° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (d, J=9.4 Hz, 1H), 7.05 (d, J=3.1 Hz,1H), 6.98-6.88 (m, 3H), 6.38 (s, 2H), 4.46 (m, 2H), 4.04 (t, J=6.2 Hz,2H), 2.99-2.92 (m, 6H), 2.87 (s, 3H), 2.86 (s, 3H), 1.82 (m, 6H), 1.61(m, 2H), 1.44 (m, 6H), 1.03 (m, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.7, 152.4, 152.2, 146.7, 133.1, 125.3,121.4, 112.1, 109.2, 108.3, 67.6, 44.6, 42.8, 42.4, 39.53, 39.49, 29.7,29.0, 28.7, 27.4, 26.7, 26.3, 25.6, 21.3, 14.2;

MS (APCI) m/z 569 (M+H)⁺;

Anal. Calcd. for C₂₅H₄₀N₆O₅S₂: % C, 52.80; % H, 7.09; % N, 14.78. Found:% C, 52.61; % H, 7.13; % N, 14.52.

Example 48N-(6-{4-Amino-1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy}hexyl)acetamide

A modification of the method described in Park K of Example 45 wasfollowed using acetyl chloride (135 μL, 1.91 mmol) in lieu ofmethanesulfonic anhydride andN-{4-[4-amino-7-(6-aminohexyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide(0.85 g, 1.7 mmol) as the starting material. The crude product waspurified by column chromatography on silica gel (eluting sequentiallywith 90:10 and 80:20 dichloromethane:methanol). The resulting whitepowder was stirred with water, isolated by filtration, and dissolved in50:50 dichloromethane:methanol. The solution was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting solid was recrystallized from acetonitrile, and the crystalswere dissolved in dichloromethane:methanol, concentrated under reducedpressure, and further dried overnight under high vacuum at 60° C. toprovide 0.30 g ofN-(6-{4-amino-1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy}hexyl)acetamideas a white powder, mp 168-172° C.

¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=9.4 Hz, 1H), 7.78 (m, 1H), 7.04 (d,J=2.5 Hz, 1H), 6.98 (m, 1H), 6.89 (dd, J=9.4, 2.5 Hz, 1H), 6.35 (s, 2H),4.46 (m, 2H), 4.03 (t, J=6.2 Hz, 2H), 3.04-2.96 (m, 4H), 2.86 (m, 5H),1.78 (m, 9H), 1.62 (m, 2H), 1.42 (m, 6H), 1.03 (t, J=7.5 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 169.2, 157.8, 152.4, 152.3, 146.9, 133.1,125.3, 121.4, 112.1, 109.2, 108.4, 67.6, 44.6, 42.4, 39.5, 38.8, 29.5,29.0, 28.7, 27.4, 26.6, 25.7, 23.0, 21.3, 14.2;

MS (APCI) m/z 533 (M+H)⁺;

Anal. Calcd. for C₂₆H₄₀N₆O₄S.0.25 H₂O: % C, 58.13; % H, 7.60; % N,15.64; % S, 5.97.

Found: % C, 57.90; % H, 7.69; % N, 15.54; % S, 6.23.

Example 49N-(2-{4-Amino-2-ethoxymethyl-7-[6-(methanesulfonylamino)hexyloxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide

Part A

Under a nitrogen atmosphere, a solution of(2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (6.5 g,17.5 mmol), prepared in Part A of Example 45, in dichloromethane (200mL) was cooled to 0° C.; triethylamine (4.87 mL, 35.0 mmol) and acetylchloride (1.37 mL, 19.2 mmol) were sequentially added. The reaction wasstirred at 0° C. for 30 minutes, allowed to warm to ambient temperature,and stirred for three hours. The reaction was washed with saturatedaqueous sodium bicarbonate (2×) and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to provideN-[1,1-dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]acetamideas a yellow powder.

Part B

The method described in Part C of Example 45 was used to convert thematerial from Part B to 6.16 g ofN-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]acetamide,obtained as an orange solid.

Part C

A modification of the method described in Part D of Example 45 wasfollowed usingN-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]acetamide(6.16 g, 21.0 mmol) as the starting material. A solution of theintermediate in ethanol was heated at reflux for 24 hours. Sodiumhydroxide (1.25 g) and water (25 mL) were added, and the reaction washeated at reflux for an additional 32 hours. The mixture was allowed tocool to ambient temperature, and the solvent was removed under reducedpressure. The residue was partitioned between dichloromethane andsaturated aqueous sodium bicarbonate. The organic layer was separatedand washed sequentially with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting orange solid was purified by columnchromatography on silica gel (eluting with 95:5dichloromethane:methanol) to provide 4.79 g ofN-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamideas a yellow solid.

Part D

The method described in Part E of Example 45 was used to convertN-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (4.79 g, 10.7 mmol) toN-[2-(2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide,obtained as a yellow solid.

Part E

The method described in Part L of Example 2 was followed. The materialfrom Part D was treated with tert-butyl 6-iodohexylcarbamate (3.86 g,11.8 mmol), and the reaction was complete in four hours. The crudeproduct was purified by column chromatography on silica gel (elutingsequentially with 95:5 and 92.5:7.5 dichloromethane:methanol), and theresulting solid was dried overnight under high vacuum to provide 4.69 gof tert-butyl{6-[1-(2-acetylamino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yloxy]hexyl}carbamateas an off-white solid.

Part F

A modification of the method described in Part M of Example 2 was usedto convert tert-butyl{6-[1-(2-acetylamino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yloxy]hexyl}carbamate(4.69 g, 8.44 mmol) to tert-butyl{6-[1-(2-acetylamino-2-methylpropyl)-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-7-yloxy]hexyl}carbamate,obtained as a orange solid. The reaction was complete in one hour, andthe product was used without purification.

Part G

The method described in Part I of Example 45 was used to convert thematerial from Part F to 4.85 g of tert-butyl{6-[1-(2-acetylamino-2-methylpropyl)-4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yloxy]hexyl}carbamate,obtained as an orange solid.

Part H

A modification of the method described in Part O of Example 2 was usedto deprotect the material from Part G with hydrochloric acid in ethanol(100 mL of 3 M). Following the treatment of the crude product withammonium hydroxide and the remainder of the work-up procedure, 3.64 g ofN-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamidewere obtained as a tan solid and used without further purification.

Part I

A modification of the method described in Part K of Example 45 wasfollowed usingN-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide(1.2 g, 2.5 mmol) as the starting material. The reaction was run in1-methyl-2-pyrrolidone (55 mL), and after completion, the reaction waspoured into deionized water (400 mL) and stirred over three days. Themixture was extracted with dichloromethane (3×200 mL), and the combinedextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was dissolved indiethyl ether (100 mL) and treated with a solution of hydrochloric acidin ethanol. A solid formed, and the diethyl ether was decanted. Thesolid was partitioned between dichloromethane and dilute ammoniumhydroxide. The aqueous layer was separated and extracted withdichloromethane (3×100 mL). The combined organic fractions were washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting orange oil was triturated with diethylether overnight to form a solid, which was isolated by filtration andpurified by column chromatography on silica gel (eluting with 92:8dichloromethane:methanol). The resulting solid was dried overnight underhigh vacuum at 60° C. to provide 0.47 g ofN-(2-{4-amino-2-ethoxymethyl-7-[6-(methanesulfonylamino)hexyloxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamideas an off-white powder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 7.01(d, J=2.7 Hz, 1H), 6.92 (m, 1H), 6.84 (m, 1H), 6.50 (s, 2H), 4.93 (s,2H), 4.69 (s, 2H), 4.03 (m, 2H), 3.50 (q, J=7.0 Hz, 2H), 2.92 (m, 2H),2.86 (s, 3H), 1.80 (s, 3H), 1.74 (m, 2H), 1.48-1.38 (m, 6H), 1.18 (br s,6H), 1.11 (t, J=7.0 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 170.3, 157.9, 152.6, 149.8, 147.6, 135.0,125.3, 122.6, 111.4, 109.6, 108.4, 67.6, 65.7, 64.6, 55.0, 51.1, 42.8,29.7, 29.0, 26.3, 25.9, 25.6, 24.0, 15.3; MS (APCI) m/z 549 (M+H)⁺;

Anal. Calcd. for C₂₆H₄₀N₆O₅S.0.70 H₂O: % C, 55.64; % H, 7.44; % N,14.97. Found: % C, 55.98; % H, 7.29; % N, 14.87.

Example 50N-(2-{7-[6-(Acetylamino)hexyloxy]-4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide

A modification of the method described in Part K of Example 45 wasfollowed usingN-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide(1.2 g, 2.5 mmol) as the starting material and acetyl chloride (200 μL,3 mmol) in lieu of methanesulfonic anhydride. Following chromatographicpurification, the solid was recrystallized from acetonitrile, and thecrystals were dissolved in dichloromethane:methanol, concentrated underreduced pressure, and further dried under high vacuum at 60° C. toprovide 0.47 g ofN-(2-{7-[6-(acetylamino)hexyloxy]-4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamideas a white powder, mp 190-192° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J=9.0 Hz, 1H), 7.77 (m, 1H), 7.70(s, 1H), 7.01 (d, J=2.6 Hz, 1H), 6.83 (dd, J=9.0, 2.6 Hz, 1H), 6.50 (s,2H), 4.93 (s, 2H), 7.69 (s, 2H), 4.02 (t, J=6.4 Hz, 2H), 3.50 (m, 2H),3.01 (m, 2H), 1.80 (s, 3H), 1.77 (s, 3H), 1.74 (m, 2H), 1.41 (m, 6H),1.18 (br s, 6H), 1.11 (t, J=7.0, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 170.3, 169.2, 157.9, 152.6, 149.8, 147.6,135.0, 125.4, 122.6, 111.4, 109.6, 108.4, 67.6, 65.7, 64.6, 55.0, 51.6,38.8, 29.5, 29.0, 26.6, 25.9, 25.7, 24.0, 23.0, 15.3;

MS (APCI) m/z 513 (M+H)⁺;

Anal. Calcd. for C₂₇H₄₀N₆O₄.0.8H₂O: % C, 61.53; % H, 7.96; % N, 15.95.Found: % C, 61.65; % H, 8.05; % N, 15.88.

Example 51N-[2-(4-Amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)ethyl]methanesulfonamide

Part A

The methods described in Parts A-H, M, and N of Example 2 were followedusing 3-benzyloxyaniline in lieu of 4-benzyloxyaniline. The crudeproduct was recrystallized from acetonitrile to provide7-benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine asa flocculent, white solid, mp 188-189° C.

¹H NMR (300 MHz, DMSO-d₆): δ 7.91 (d, J=9.1 Hz, 1H), 7.52-7.30 (m, 5H),7.13 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.9, 2.6 Hz, 1H), 6.53 (s, 2H), 5.21(s, 2H), 4.74 (s, 2H), 4.49-4.44 (m, 2H), 3.54 (q, J=7.0 Hz, 2H),1.92-1.78 (m, 2H), 1.15 (t, J=6.9 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H).

¹³C NMR (75 MHz, DMSO-d₆): δ 157.3, 152.3, 148.1, 146.9, 137.2, 133.4,128.4, 127.7, 127.6, 124.9, 121.3, 111.9, 108.9, 108.7, 69.1, 65.3,64.2, 46.6, 23.0, 14.9, 10.7.

MS (ESI) m/z 391.2134 (391.2117 calcd for C₂₃H₂₆N₄O₂, M+H⁺).

Anal. Calcd. for C₂₃H₂₆N₄O₂: % C, 70.75; % H, 6.71; % N, 14.35. Found: %C, 70.49; % H, 6.57; % N, 14.22.

Part B

7-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(3.9 g, 9.99 mmol) was mixed with ethanol and added to a Parr flaskcharged with 10% palladium on carbon (0.390 g) in ethanol. The flask wasplaced under hydrogen pressure and shaken for 18 hours. The reactionmixture was filtered through a layer of CELITE filter aid, and thefilter cake was washed with warm DMF. The filtrate was concentratedunder reduced pressure, and the residue was recrystallized from methanolto yield 2.4 g of4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol as awhite solid, mp>250° C.

¹H NMR (300 MHz, DMSO-d₆): δ 9.50 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 6.96(d, J=2.5 Hz, 1H), 6.81 (dd, J=8.8, 2.6 Hz, 1H), 6.45 (s, 2H), 4.73 (s,2H), 4.47-4.41 (m, 2H), 3.54 (q, J=7.0 Hz, 2H), 1.92-1.78 (m, 2H), 1.15(t, J=6.9 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆): δ 156.4, 152.1, 147.7, 147.1, 133.6, 124.5,121.2, 112.0, 109.8, 107.9, 65.2, 64.2, 46.6, 23.0, 14.9, 10.7;

Anal. Calcd. for C₁₆H₂₀N₄O₂: % C, 63.98; % H, 6.71; % N, 18.65. Found: %C, 63.71; % H, 6.48; % N, 18.53.

Part C

The method described in Part L of Example 2 was used to treat4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (1.89 g,6.29 mmol) with cesium carbonate (4.10 g, 12.6 mmol) and tert-butyl2-iodoethylcarbamate (1.79 g, 6.60 mmol). Following chromatographicpurification, the product was recrystallized from acetonitrile toprovide 1.26 g of tert-butyl[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)ethyl]carbamateas a flocculent, white solid.

Part D

The method described in Part O of Example 2 was used to treat thematerial from Part C with 4 M hydrochloric acid in ethanol to provide7-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine,which was used without purification.

Part E

A suspension of7-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.570 g, 1.66 mmol) in dichloromethane (11 mL) was cooled to 0° C.Methanesulfonic anhydride (0.303 g, 1.74 mmol) was added, and themixture was stirred for 16 hours and allowed to warm to ambienttemperature. Saturated aqueous sodium carbonate (25 mL) was added, andthe mixture was stirred for 20 minutes. The aqueous layer was separatedand extracted with chloroform (3×50 mL). The combined organic fractionswere washed sequentially with water and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting white solid was purified by column chromatography on silicagel (eluting with chloroform:methanol:ammonium hydroxide ranging inratios from 99.6:0.36:0.04 to 97:2.7:0.3) and subsequentrecrystallization from acetonitrile to yield 0.500 g ofN-[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]methanesulfonamideas white, granular powder mp 182-184.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (d, J=9.1 Hz, 1H), 7.31 (t, J=6.2 Hz,1H), 7.08 (d, J=3.2 Hz, 1H), 6.95 (dd, J=9.1, 2.6 Hz, 1H), 6.54 (s, 2H),4.75 (s, 2H), 4.50-4.45 (m, 2H), 4.13 (t, J=5.6 Hz, 2H), 3.55 (q, J=7.0Hz, 2H), 3.39 (q, J=5.8 Hz, 2H), 2.98 (s, 3H), 1.93-1.79 (m, 2H), 1.16(t, J=7.0 Hz, 3H), 1.01 (t, J=7.3 Hz, 3H);

MS (APCI) m/z 422.1864 (422.1862 calcd for C₁₉H₂₇N₅O₄S, M+H).

Anal. Calcd. for C₁₉H₂₇N₅O₄S: % C, 54.14; % H, 6.46; % N, 16.61; % S,7.61. Found: % C, 54.23; % H, 6.50; % N, 16.66; % S, 7.63.

Example 521-[4-Amino-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-one

Part A

The methods described in Parts E, F, and G of Example 1 were used toconvert 7-benzyloxy-4-chloro-3-nitroquinoline, prepared in Parts A-D ofExample 1, to7-benzyloxy-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline.2-Phenoxyethylamine was used in lieu of isobutylamine in Part E, andtriethyl orthopropionate was used in lieu of trimethyl orthobutyrate inPart G.

Part B

The method described in Part J of Example 1 was used to convert7-benzyloxy-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline to2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol.

Part C

A suspension of2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.0 g, 3.0mmol) and cesium carbonate (1.49 g, 4.57 mmol) in DMF was stirred for 15minutes; 1-bromopinacolone (0.6 mL, 4.5 mmol) was added dropwise. Thereaction was heated at 65° C. and stirred for 20 hours, and then thesolvent was removed under reduced pressure. The residue was dissolved indichloromethane, and the resulting solution was washed sequentially withwater (3×) and brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide 1.3 g of1-[2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-oneas an orange solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.44 (d, J=9.3 Hz, 1H), 7.45(d, J=2.5 Hz, 1H), 7.34 (dd, J=9.1, 2.5 Hz, 1H), 7.23-7.18 (m, 2H),6.91-6.86 (m, 1H), 6.78-6.75 (m, 2H), 5.32 (s, 2H), 5.05-4.98 (m, 2H),4.44 (t, J=5.0 Hz, 2H), 3.08 (q, J=7.3 Hz, 2H), 1.43 (t, J=7.6 Hz, 3H),1.23 (s, 9H).

Part D

The method described in Part M of Example 2 was used to oxidize1-[2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-one(1.3 g, 3.0 mmol) to 1.4 g of1-[2-ethyl-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-one,which was isolated as an orange solid and used without purification.

¹H NMR (300 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.55 (d, J=9.2 Hz, 1H), 8.12(d, J=2.2 Hz, 1H), 7.48 (dd, J=9.3, 3.0 Hz, 1H), 7.23-7.17 (m, 2H),6.91-6.86 (m, 1H), 6.76-6.73 (m, 2H), 5.38 (s, 2H), 5.04-4.99 (m, 2H),4.44 (t, J=5.0 Hz, 2H), 3.07 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H),1.24 (s, 9H).

Part E

Ammonium hydroxide (6 mL) was added to a solution of the material fromPart D in dichloromethane (20 mL). p-Toluenesulfonyl chloride (0.629 g,3.30 mmol) was added in two portions, and the mixture was stirred for 16hours. The mixture was then diluted with dichloromethane and water. Theaqueous layer was separated and extracted twice with chloroform. Thecombined organic fractions were washed sequentially with water andbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting white solid was recrystallized fromacetonitrile twice to yield 0.360 g of1-[4-amino-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo-[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-oneas feathery, white needles, mp 238-239° C. (decomposition).

¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=9.2 Hz, 1H), 7.24-7.2 (m, 2H),6.96 (d, J=2.5 Hz, 1H), 6.92-6.86 (m, 2H), 6.84-6.80 (m, 2H), 6.36 (s,2H), 5.19 (s, 2H), 4.96-4.88 (m, 2H), 4.40 (t, J=5.0 Hz, 2H), 3.01 (q,J=7.5 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.20 (s, 9H);

MS (APCI) m/z 447.2402 (447.2396 calcd for C₂₆H₃₀N₄O₃, M+H).

Anal. Calcd. for C₂₆H₃₀N₄O₃.1.0H₂O: % C, 67.22; % H, 6.94; % N, 12.06.Found: % C, 67.29; % H, 6.81; % N, 12.03.

Example 532-Ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

The methods described in Parts A-D of Example 30 were used to convert7-benzyloxy-N⁴-(2-phenoxyethyl)quinoline-3,4-diamine to2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline.In Part D, after the reaction mixture was filtered, the filtrate wasallowed to stand for three days. Crystals formed and were isolated byfiltration and washed with diethyl ether. The filtrate was concentratedunder reduced pressure, and the resulting oil with triturated with amixture of ethyl acetate and water. The resulting solid was isolated byfiltration, washed with diethyl ether, and combined with the crystalsisolated from the reaction mixture. The combined solids wererecrystallized from methanol, isolated by filtration, washed with coldhexanes, and dried overnight under high vacuum at 70° C. to provide2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolineas a white solid, mp 190-191° C.

Anal. Calcd. for C₂₆H₂₈N₄O₄: % C, 67.81; % H, 6.13; % N, 12.17. Found: %C, 67.44; % H, 6.20; % N, 12.05.

Part B

The method described in Part E of Example 30 was used to convert2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline(0.855 g, 1.86 mmol) to 0.92 g of2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline.

Part C

Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.35 mL, 2.9mmol) was added dropwise to a solution of the material from Part B inanhydrous dichloromethane (335 mL), and the reaction was stirred for twohours. The solvent was removed under reduced pressure. The residue wasdiluted with methanol (23 mL), and a solution of sodium methoxide (0.17mL, 2.9 mmol, 25% in methanol) was slowly added. The reaction wasstirred overnight, and a precipitate formed. The precipitate wasisolated by filtration, washed with three times with cold hexanes, andrecrystallized from ethyl acetate to provide 0.495 g of2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, mp 208-209° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=9.3 Hz, 1H), 7.22 (m, 2H), 7.05(d, J=2.7 Hz, 1H), 6.90 (t, J=2.7 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.82(d, J=0.9 Hz, 1H), 6.79 (d, J=0.9 Hz, 1H), 6.39 (s, 2H), 4.91 (s, 4H),4.39 (t, J=4.8 Hz, 2H), 3.54 (m, 8H), 3.01 (q, J=7.5 Hz, 2H), 1.40 (t,J=7.5 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 166.5, 158.2, 157.0, 154.4, 152.3, 146.8,133.4, 129.8, 125.3, 121.7, 121.4, 114.6, 111.8, 109.6, 108.8, 66.7,66.4, 66.3, 45.2, 44.6, 42.0, 20.3, 12.2;

MS (EI) m/z 476.2282 (476.2298 calcd for C₂₆H₂₉N₅O₄).

Anal. Calcd for C₂₆H₂₉N₅O₄: % C, 65.67; % H, 6.15; % N, 14.73. Found: %C, 65.48; % H, 6.01; % N, 14.59.

Example 541-(2-Methylpropyl)-2-propyl-7-(tetrahydropyran-2-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

The methods described in Parts L-N of Example 2 were used to treat1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol. In Part L,2-(bromomethyl)tetrahydro-2H-pyran was used as the alkylating agent. Thecrude product was recrystallized from acetonitrile to yield1-(2-methylpropyl)-2-propyl-7-(tetrahydropyran-2-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amineas tan crystals, mp 126° C. (decomposition).

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.6 Hz, 1H), 7.03 (d, J=3.0 Hz,1H), 6.90 (dd, J=9.2, 2.9 Hz, 1H), 6.37 (s, 2H), 4.28 (d, J=7.6 Hz, 2H),4.02-3.86 (m, 3H), 3.71-3.61 (m, 1H), 3.46-3.34 (m, 1H), 2.86 (t, J=7.8Hz, 2H), 2.21-2.05 (m, 1H), 1.90-1.77 (m, 3H), 1.72-1.63 (m, 1H),1.58-1.27 (m, 4H), 1.02 (t, J=7.4 Hz, 3H), 0.91 (d, J=6.7 Hz, 6H);

MS (APCI) m/z 397.2600 (397.2604 calcd for C₂₃H₃₂N₄O₂, M+H).

Anal. Calcd. for C₂₃H₃₂N₄O₂.0.75H₂O: % C, 67.37; % H, 8.23; % N, 13.66.Found: % C, 67.06; % H, 8.06; % N, 13.52.

Example 551-(2-Methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

3-Hydroxytetrahydrofuran (0.375 mL, 4.64 mmol) was added to a suspensionof 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (1.0 g,3.5 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) in THF. Diisopropylazodicarboxylate (1.1 mL, 5.6 mmol) was added dropwise over a period ofthree minutes, and the reaction was stirred for 48 hours. The solventwas removed under reduced pressure, the residue was purified by columnchromatography on silica gel (eluting with 98:2dichloromethane:methanol) to provide 1.1 g of1-(2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolineas an off-white, crystalline solid.

Part B

The method described in Part M of Example 2 was used to treat1-(2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline(1.1 g, 3.1 mmol) with mCPBA (1.07 g, 3.72 mmol). The crude product waspurified by column chromatography on silica gel to afford 0.588 g of1-(2-methylpropyl)-5-oxido-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolineas a yellow solid.

Part C

The method described in Part E of Example 52 was used to aminate thematerial from Part B. The crude product was recrystallized fromacetonitrile to afford 0.242 g of1-(2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amineas white needles, mp 178-182° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=9.0 Hz, 1H), 7.02 (d, J=2.7 Hz,1H), 6.89 (dd, J=8.9, 2.7 Hz, 1H), 6.40 (s, 2H), 5.13-5.09 (m, 1H), 4.29(d, J=7.3 Hz, 2H), 3.96-3.73 (m, 4H), 2.86 (t, J=7.5 Hz, 2H), 2.33-1.97(m, 3H), 1.84 (sextet, J=7.5 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H), 0.91 (d,J=6.4 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 155.6, 152.6, 152.0, 146.4, 132.7, 125.2,121.4, 112.0, 109.2, 109.0, 76.9, 72.3, 66.4, 51.2, 32.5, 28.7, 28.5,20.9, 19.1, 13.8;

MS (APCI) m/z 369.2298 (369.2291 calcd for C₂₁H₂₈N₄O₂, M+H).

Anal. Calcd. for C₂₁H₂₈N₄O₂: % C, 68.45; % H, 7.66; % N, 15.20. Found: %C, 68.11; % H, 7.87; % N, 15.01.

Example 562-(2-Methoxyethyl)-1-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine

The methods described in Parts A and B of Example 51 were used toprepare 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol,which was treated according to the methods described in Example 55. Thecrude product was purified by column chromatography on silica gel andsubsequent recrystallization from 2-propanol to afford2-(2-methoxyethyl)-1-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder, mp 192-194° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=9.2 Hz, 1H), 7.02 (d, J=2.6 Hz,1H), 6.89 (dd, J=9.0, 2.6 Hz, 1H), 6.41 (s, 2H), 5.14-5.10 (m, 1H),4.46-4.41 (m, 2H), 3.97-3.74 (m, 6H), 3.30 (s, 3H), 3.16 (t, J=6.8 Hz,2H), 2.33-2.21 (m, 1H), 2.08-1.98 (m, 1H), 1.87-1.74 (m, 2H), 0.98 (t,J=7.4 Hz, 3H);

MS (APCI) m/z 371.2074 (371.2083 calcd for C₂₀H₂₆N₄O₃, M+H).

Anal. Calcd. for C₂₀H₂₆N₄O₃: % C, 64.85; % H, 7.07; % N, 15.12. Found: %C, 64.88; % H, 7.03; % N, 15.20.

Examples 57-92

An acid chloride (1.1 equivalents) was added to a culture tubecontaining a solution of7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine(4.4 mg/mL) in chloroform (5 mL). The culture tubes were capped andplaced on a shaker overnight (18 hours). The volatiles were removed byvacuum centrifugation. The compounds were purified by preparative highperformance liquid chromatography (prep HPLC) using a Waters FractionLynx automated purification system. The prep HPLC fractions wereanalyzed using a Micromass LC-TOFMS, and the appropriate fractions werecentrifuge evaporated to provide the trifluoroacetate salt of thedesired compound. (Column: Phenomenex Luna C18(2), 21.2×50 mm, 10 micronparticle size, 100 Å pore; flow rate: 25 mL/min.; non-linear gradientelution from 5-95% B in 9 min, then hold at 95% B for 2 min., where A is0.05% trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile; fraction collection by mass-selective triggering.)The table below shows the structure made in each example and theobserved accurate mass for the isolated trifluoroacetate salt.

Examples 57-92

Measured Mass Example R (M + H) 57

424.2727 58

426.2879 59

440.3047 60

456.2622 61

460.2736 62

466.2288 63

466.3162 64

474.2877 65

478.2616 66

480.2419 67

480.3356 68

485.2668 69

485.2667 70

486.2862 71

488.3015 72

490.2820 73

495.2273 74

496.2515 75

498.3105 76

500.3048 77

502.3173 78

504.2619 79

504.2990 80

506.2589 81

510.2873 82

518.2742 83

518.3122 84

518.3502 85

520.2934 86

520.2920 87

524.2440 88

527.2756 89

528.2599 90

528.2592 91

532.3278 92

544.2535

Examples 93-129

The method described for Examples 57-92 was used to treat1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith acid chlorides. The table below shows the structure made in eachexample and the observed accurate mass for the isolated trifluoroacetatesalt.

Examples 93-129

Ex- Measured am- Mass ple R (M + H)  93

478.3181  94

480.3352  95

494.3478  96

510.3051  97

514.3151  98

520.2748  99

520.3622 100

528.3341 101

532.3076 102

534.2899 103

534.3823 104

539.3121 105

539.3130 106

540.3336 107

542.3503 108

544.3304 109

544.3291 110

549.2761 111

552.3552 112

554.3510 113

556.3687 114

558.3102 115

558.3455 116

560.3093 117

564.3351 118

572.3240 119

572.3608 120

572.3984 121

574.3419 122

574.3412 123

578.2916 124

582.3076 125

582.3096 126

582.2361 127

586.3799 128

598.3027 129

612.4310

Examples 130-161

The method described for Examples 57-92 was used to treat8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith acid chlorides. The table below shows the structure made in eachexample and the observed accurate mass for the isolated trifluoroacetatesalt.

Examples 130-161

Measured Mass Example R (M + H) 130

414.2480 131

428.2674 132

444.2262 133

448.2362 134

454.1902 135

454.2825 136

462.2513 137

466.2257 138

468.2071 139

468.2960 140

473.2296 141

474.2487 142

476.2667 143

478.2455 144

478.2453 145

483.1922 146

484.2175 147

486.2725 148

488.2654 149

490.2791 150

492.2255 151

492.2588 152

494.2204 153

498.2528 154

506.2372 155

506.2751 156

508.2549 157

508.2546 158

516.2205 159

516.2219 160

516.1549 161

520.2924

Examples 162-189

The method described for Examples 57-92 was used to treat7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith sulfonyl chlorides. The table below shows the structure made ineach example and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 162-189

Measured Mass Example R (M + H) 162

448.2388 163

462.2542 164

463.2517 165

476.2714 166

514.2286 167

521.2303 168

521.2302 169

521.2334 170

522.2527 171

526.2491 172

532.2197 173

536.1563 174

538.2829 175

540.2260 176

546.2551 177

546.2537 178

547.2464 179

555.2372 180

564.2252 181

564.1624 182

568.2946 183

570.3129 184

570.3125 185

574.2169 186

580.2222 187

588.2659 188

589.2966 189

635.2490

Examples 190-217

The method described for Examples 57-92 was used to treat1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith sulfonyl chlorides. The table below shows the structure made ineach example and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 190-217

Measured Mass Example R (M + H) 190

502.2851 191

516.2997 192

517.2976 193

530.3141 194

550.2875 195

556.2460 196

568.2739 197

569.2917 198

575.2827 199

575.2785 200

580.2991 201

590.2044 202

592.3352 203

594.2772 204

600.3042 205

601.2969 206

609.2883 207

618.2733 208

622.3428 209

624.3610 210

624.3606 211

626.3162 212

628.2621 213

634.2709 214

642.3131 215

643.3466 216

689.2985 217

696.2326

Examples 218-242

The method described for Examples 57-92 was used to treat8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith sulfonyl chlorides. The table below shows the structure made ineach example and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 218-242

Measured Example R Mass (M + H) 218

436.2036 219

450.2162 220

451.2139 221

464.2341 222

484.2017 223

502.1901 224

503.2099 225

509.1982 226

509.1957 227

509.1964 228

510.2191 229

514.2129 230

520.1815 231

524.1172 232

526.2491 233

535.2117 234

543.2015 235

552.1878 236

558.2752 237

558.2780 238

560.2318 239

562.1780 240

568.1868 241

577.2585 242

623.2094

Examples 243-284

The method described for Examples 57-92 was used to treat7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith isocyanates or carbamoyl chlorides. The table below shows thestructure made in each example and the observed accurate mass for theisolated trifluoroacetate salt.

Examples 243-284

Measured Mass Example R (M + H) 243

441.3011 244

455.3159 245

427.2842 246

475.2837 247

481.3302 248

485.2899 249

489.2988 250

453.2988 251

491.2608 252

455.3156 253

500.2784 254

503.2751 255

503.3134 256

503.3156 257

503.3123 258

467.3150 259

505.2916 260

469.2950 261

509.2340 262

511.3764 263

515.3130 264

517.2918 265

517.3308 266

518.3246 267

483.3452 268

521.2693 269

521.2685 270

525.2961 271

489.2985 272

528.3100 273

533.3608 274

543.2682 275

543.2704 276

543.2021 277

547.3023 278

549.3399 279

553.3261 280

557.2203 281

567.3111 282

567.3104 283

567.3091 284

581.3271

Examples 285-322

The method described for Examples 57-92 was used to treat1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith isocyanates or carbamoyl chlorides. The table below shows thestructure made in each example and the observed accurate mass for theisolated trifluoroacetate salt.

Examples 285-322

Measured Ex- Mass ample R (M + H) 285

495.3449 286

509.3607 287

509.3616 288

481.3298 289

535.3751 290

539.3303 291

543.3445 292

507.3424 293

509.3565 294

554.3253 295

557.3626 296

557.3613 297

557.3580 298

521.3593 299

559.3403 300

523.3367 301

563.2794 302

565.4229 303

569.3617 304

571.3754 305

572.3731 306

573.3036 307

537.3932 308

575.3166 309

543.3455 310

582.3604 311

582.3961 312

587.4092 313

597.3188 314

597.3159 315

597.2525 316

601.3510 317

607.3763 318

611.2715 319

621.3568 320

621.3579 321

621.3558 322

635.3752

Examples 323-365

The method described for Examples 57-92 was used to treat8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-aminewith isocyanates or carbamoyl chlorides. The table below shows thestructure made in each example and the observed accurate mass for theisolated trifluoroacetate salt.

Examples 323-365

Measured Ex- Mass ample R (M + H) 323

429.2625 324

443.2764 325

443.2767 326

415.2455 327

463.2470 328

469.2912 329

473.2515 330

477.2578 331

441.2581 332

479.2237 333

443.2777 334

488.2429 335

491.2392 336

491.2771 337

491.2736 338

491.2767 339

455.2770 340

493.2577 341

457.2596 342

497.1951 343

499.3385 344

503.2771 345

505.2913 346

506.2881 347

507.2170 348

471.3080 349

509.2324 350

509.2308 351

513.2603 352

477.2582 353

516.2743 354

516.3096 355

521.3214 356

527.2079 357

531.2340 358

531.2343 359

535.2642 360

541.2932 361

545.1819 362

555.2700 363

555.2697 364

555.2692 365

569.2889

Example 3664-Amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ylisopropylcarbamate

Part A

The methods described in Parts A-I of Example 2 were followed using3-benzyloxyaniline in lieu of 4-benzyloxyaniline and methoxypropionylchloride in lieu of ethoxyacetyl chloride.2-(2-Methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (2.0 g, 7.0mmol), 4-(dimethylamino)pyridine (0.085 g, 0.70 mmol), andtetrahydrofuran (70 mL) were combined, and the mixture was cooled to 7°C. with an ice/water bath. Isopropyl isocyanate (0.689 mL, 7.01 mmol)was added dropwise to the mixture. After 20 minutes the cooling bath wasremoved and the reaction was stirred for an additional 24 hours.Analysis by HPLC indicated that no product had formed. Di-butyltindilaurate (1 drop) was added, and the reaction was stirred at ambienttemperature for 2.5 hours and then heated at reflux for 48 hours. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in dichloromethane. The organic fraction was washedsequentially with water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. Purification bycolumn chromatography on silica gel (eluting with achloroform:methanol:ammonium hydroxide gradient) provided 1.97 g of2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ylisopropylcarbamate as a white solid.

Part B

2-(2-Methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ylisopropylcarbamate (1.89 g, 5.10 mmol) was dissolved in chloroform (41mL). 3-Chloroperoxybenzoic acid (60% pure, 1.60 g, 5.56 mmol) was addedin one portion. After 30 minutes the golden solution was diluted withammonium hydroxide (41 mL), and p-toluenesulfonyl chloride (0.927 g,4.86 mmol) was added. The reaction was stirred for 1.5 hours. The layerswere separated and the aqueous fraction was extracted withdichloromethane. The organic fractions were combined, washedsequentially with water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The solid residue wasrecrystallized from acetonitrile to provide 0.986 g of4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ylisopropylcarbamate as a granular, peach-colored solid, mp 144.0-146.0°C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (d, J=9.0 Hz, 1H), 7.68 (d, J=7.62 Hz,1H), 7.22 (d, J=2.43 Hz, 1H), 7.01 (dd, J=2.5, 8.9 Hz, 1H), 6.53 (s,2H), 4.48-4.43 (m, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.67 (sextet, J=6.8 Hz,1H), 3.28 (s, 3H), 3.17 (t, J=6.7 Hz, 2H), 1.81 (sextet, J=7.4 Hz, 2H),1.14 (d, J=6.6 Hz, 6H), 0.97 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 153.5, 152.1, 150.5, 149.5, 145.7, 132.2,126.0, 120.5, 117.4, 116.0, 111.9, 70.1, 58.1, 46.1, 42.6, 27.1, 23.0,22.4, 10.6;

MS (ESI) m/z 386.2177 (386.2192 calcd for C₂₀H₂₇N₅O₃, M+H).

Anal. Calcd. for C₂₀H₂₇N₅O₃: % C, 62.32; % H, 7.06; % N, 18.17. Found: %C, 62.02; % H, 6.94; % N, 17.92.

Example 3674-Amino-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ylmethanesulfonate

Part A

2-Ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.5 g, 4.5mmol), chloroform (45 mL), and triethylamine (0.697 mL, 5.00 mmol) werecombined. Methanesulfonyl chloride (0.348 mL, 4.50 mmol) was addeddropwise to the mixture; a flocculent precipitate formed. The reactionwas stirred for 72 hours and then quenched with methanol. The volatileswere removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluting with adichloromethane:methanol gradient) to provide 0.628 g of2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ylmethanesulfonate as a white solid.

Part B

2-Ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ylmethanesulfonate (0.625 g, 1.52 mmol) was dissolved in chloroform (15mL). 3-Chloroperoxybenzoic acid (60% pure, 0.437 g, 1.52 mmol) was addedin one portion, and the reaction was stirred for 25 minutes. Ammoniumhydroxide (25 mL) was added. A precipitate formed, and the reaction wasstirred until the precipitate dissolved. p-Toluenesulfonyl chloride(0.290 g, 1.52 mmol) was added in one portion, and the reaction mixturewas stirred for an additional 16 hours. The layers were separated, andthe aqueous fraction was extracted with dichloromethane followed bychloroform. The organics were combined, washed sequentially with waterand brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. Purification by column chromatography on silica gel(eluting with a chloroform:methanol:ammonium hydroxide gradient)followed by recrystallization from acetonitrile provided 0.150 g of4-amino-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ylmethanesulfonate as an orange solid, mp 213.0-214.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.5 Hz,1H), 7.23-7.17 (m, 3H), 6.88 (t, J=7.3 Hz, 1H), 6.80-6.76 (m, 2H), 6.67(s, 2H), 4.98-4.94 (m, 2H), 4.42-4.39 (m, 2H), 3.39 (s, 3H), 3.04 (q,J=7.5 Hz, 2H), 1.40 (t, J=7.5 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.8, 155.3, 152.6, 147.4, 145.7, 132.4,129.5, 126.4, 122.0, 121.0, 118.2, 115.0, 114.2, 113.8, 66.4, 44.4,37.2, 20.0, 11.7;

MS (ESI) m/z 427.1444 (427.1440 calcd for C₂₁H₂₂N₄O₄S, M+H).

Anal. Calcd. for C₂₁H₂₂N₄O₄S: % C, 59.14; % H, 5.20; % N, 13.14; % S,7.52. Found: % C, 58.90; % H, 4.95; % N, 13.13; % S, 7.55.

Example 368N-(2-{4-Amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonothioyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide

Isopropyl isothiocyanate (255 μL, 2.38 mmol) was added to a stirredsuspension ofN-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide(prepared as described in Part I of Example 49, 1.02 g, 2.17 mmol) indichloromethane (100 mL) at 0° C. The mixture was stirred for 30 minutesat 0° C., then was allowed to warm to room temperature and was stirredover the weekend. The solution was concentrated under reduced pressure.The crude product was purified by flash chromatography (silica gel,gradient elution with 7.5-10% methanol in dichloromethane) followed byrecrystallization from acetonitrile. The crystals were dissolved in 1:1dichloromethane/methanol and the resulting solution was concentratedunder reduced pressure to afford a white powder that was dried undervacuum at 60° C. to yield 0.43 g ofN-(2-{4-amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonothioyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamideas a white powder, mp 110-120° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (d, J=9.0 Hz, 1H), 7.71 (s, 1H), 7.23(br s, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.85 (dd,J=9.0, 2.6 Hz, 1H), 6.51 (s, 2H), 4.94 (s, 2H), 4.70 (s, 2H), 4.22 (brs, 1H), 4.04 (t, J=6.3 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H), 1.81 (s, 3H),1.76 (m, 2H), 1.48 (m, 4H), 1.36 (m, 2H), 1.19 (s, 6H), 1.12-1.07 (m,11H);

¹³C NMR (75 MHz, DMSO-d₆) δ 181.3, 170.3, 157.9, 152.6, 149.8, 147.6,135.0, 125.3, 122.6, 111.4, 109.6, 108.4, 67.6, 65.7, 64.6, 55.0, 51.1,45.1, 43.6, 29.1, 29.0, 26.6, 25.9, 25.7, 24.0, 22.7, 15.3;

MS (APCI) m/z 572 (M+H)⁺;

Anal. calcd for C₂₉H₄₅N₇O₃S.0.40 H₂O: C, 60.16; H, 7.97; N, 16.93; S,5.54. Found: C, 60.16; H, 8.08; N, 16.84; S, 5.54.

Example 369N-(2-{4-Amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)-N′-isopropylurea

Part A

Isopropyl isocyanate (2.05 mL, 20.9 mmol) was added to a stirredsuspension of(2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine(prepared as described in Part A of Example 45, 6.95 g, 19.0 mmol) indichloromethane (200 mL) at 0° C. After approximately 30 minutes, thereaction mixture was allowed to warm to room temperature and was stirredovernight. The solvent was removed under reduced pressure to afford 8.49g ofN-(2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea.

Part B

A mixture ofN-(2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea(4.24 g, 9.39 mmol) and 5% platinum on carbon (1.0 g) in acetonitrile(700 mL) was hydrogenated at 30 psi (2.1×10⁵ Pa) overnight on a Parrapparatus. The mixture was filtered through CELITE filter agent, whichwas subsequently rinsed with acetonitrile and dichloromethane. Thefiltrate was concentrated under reduced pressure to yield 3.67 g ofN-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylureaas a pale yellow foam that was used without purification.

Part C

The material from Part B was combined withN-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylureafrom another experiment, suspended in toluene, and concentrated underreduced pressure. TheN-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea(4.57 g, 10.8 mmol) was converted intoN-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylureausing the method described in Part D of Example 45. The crude productwas purified using flash chromatography (silica gel, elution with 6%methanol in dichloromethane) to afford 3.81 g ofN-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylureaas an off white solid.

Part D

A mixture ofN-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea(3.82 g, 7.80 mmol) and 10% palladium on carbon (0.92 g) in ethanol (100mL) was hydrogenated at 50 psi (3.5×10⁵ Pa) overnight on a Parrapparatus. The mixture was filtered through CELITE filter agent and thefiltrate was concentrated under reduced pressure to yield 3.17 g ofN-{2-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylureaas a yellow solid.

Part E

Following the method described in Part L of Example 2,N-{2-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea(3.12 g, 7.80 mmol) was treated with tert-butyl 6-iodohexylcarbamate(2.81 g, 8.58 mmol) to afford 4.31 g of tert-butyl6-{[2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate.The material was used without purification in the next step.

Part F

A modification of the method described in Part M of Example 2 was usedto convert tert-butyl6-{[2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate(4.31 g, 7.20 mmol) into tert-butyl6-{[2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate,which was used without purification in the next step.

Part G

The material from Part F was converted into 4.20 g of tert-butyl6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamateusing the method described in Part I of Example 45.

Part H

A solution of tert-butyl6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate(4.20 g, 6.84 mmol) in 3 M HCl in ethanol (50 mL, 150 mmol) was heatedat reflux for five minutes, then was allowed to cool to room temperatureand was concentrated under reduced pressure. The resulting orange solidwas dissolved water and the solution was washed with dichloromethane(2×). The aqueous layer was treated with ammonium hydroxide until abasic pH was reached, then was extracted with dichloromethane (3×). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated to yield 2.98 g ofN-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylureaas a dark orange solid.

Part I

Isopropyl isocyanate (190 μL, 1.93 mmol) was added to a stirred solutionofN-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea(0.90 g, 1.75 mmol) in dichloromethane (50 mL) at 0° C. Afterapproximately 30 minutes, the solution was allowed to warm to roomtemperature. A precipitate formed and the mixture was stirred over theweekend. The solvent was removed under reduced pressure and the crudeproduct was purified by flash chromatography (silica gel, gradientelution with 8-10% methanol in dichloromethane) to provide a solid thatwas dried under vacuum at 60° C. to yield 0.34 g ofN-(2-{4-amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)-N′-isopropylureaas a tan solid, mp 205-209° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (d, J=9.1 Hz, 1H), 7.03 (d, J=2.5 Hz,1H), 6.85 (dd, J=9.0, 2.5 Hz, 1H), 6.57 (s, 2H), 5.70-5.65 (m, 3H), 5.57(d, J=7.7 Hz, 1H), 4.93 (s, 2H), 4.70 (br s, 2H), 4.04 (t, J=6.3 Hz,2H), 3.73-3.63 (m, 2H), 3.51 (q, J=7.0 Hz, 2H), 2.97 (m, 2H), 175 (m,2H), 1.44-1.35 (m, 8H), 1.12 (t, J=7.0 Hz, 3H), 1.07-0.99 (m, 16H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.9, 157.8, 157.2, 152.5, 150.2, 147.3,135.0, 125.3, 122.6, 111.5, 109.6, 108.2, 67.6, 65.6, 64.4, 54.2, 52.0,41.1, 40.9, 39.4, 30.4, 29.1, 26.6, 26.4, 25.7, 23.6, 15.3;

MS (APCI) m/z 598 (M+H)⁺;

Anal. calcd for C₃₁H₅₀N₈O₄.1.00 H₂O: C, 60.37; H, 8.50; N, 18.17. Found:C, 60.65; H, 8.66; N, 18.20.

Example 370N-(6-{[4-Amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide

Acetyl chloride (180 μL, 2.53 mmol) was added to a stirred solution ofN-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea(prepared as described in Parts A-H of Example 369, 1.18 g, 2.30 mmol)and triethylamine (0.64 mL, 4.60 mmol) in dichloromethane (100 mL) at 0°C. After approximately 20 minutes, the solution was allowed to warm toroom temperature and was stirred overnight. The solution was transferredto a separatory funnel and washed with water (2×). The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by flash chromatography (silicagel, elution with 10% methanol in dichloromethane) to yield 0.34 g ofN-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamideas a tan solid, mp 90-110° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J=9.1 Hz, 1H), 7.79 (m, 1H), 7.03(d, J=2.6 Hz, 1H), 6.85 (dd, J=9.1, 2.6 Hz, 1H), 6.57 (s, 2H), 5.70-5.65(m, 2H), 4.93 (s, 2H), 4.73 (br s, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.72 (m,1H), 3.51 (m, 2H), 3.03 (m, 2H), 1.78 (s, 3H), 1.76 (m, 2H), 1.42 (m,10H), 1.12 (t, J=7.0 Hz, 3H), 1.07-1.04 (m, 8H);

¹³C NMR (125 MHz, DMSO-d₆) δ 169.2, 158.0, 157.3, 152.5, 150.3, 147.4,135.1, 125.4, 122.6, 111.6, 109.8, 108.7, 67.8, 65.7, 64.5, 54.3, 52.2,41.0, 38.9, 29.5, 29.0, 26.6, 26.5, 25.7, 23.6, 23.0, 15.3;

MS (APCI) m/z 556 (M+H)⁺;

Anal. calcd for C₂₉H₄₅N₇O₄.0.50 H₂O: C, 61.68; H, 8.21; N, 17.36. Found:C, 61.81; H, 8.43; N, 17.22.

Example 371N-(6-{[4-Amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)methanesulfonamide

Methanesulfonic anhydride (0.34 g, 1.93 mmol) was added to a stirredsolution ofN-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea(prepared as described in Parts A-H of Example 369, 10.9 g, 1.75 mmol)and triethylamine (0.35 mL, 3.5 mmol) in dichloromethane (50 mL) at 0°C. After approximately 30 minutes, the solution was allowed to warm toroom temperature and was stirred overnight. The following morning, thesolution was cooled to 0° C. and additional methanesulfonic anhydride(0.13 g) was added. After 30 minutes, the solution was allowed to warmto room temperature. After 2 hours, the solution was transferred to aseparatory funnel and washed with water (2×) and brine. The organiclayer was dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by flash chromatography(silica gel, elution with 10% methanol in dichloromethane) followedpurification by chromatography on a HORIZON HPFC system (an automated,modular high-performance flash purification product available fromBiotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elutionwith 0-40% CMA in chloroform where CMA is a solution of 80:18:2chloroform/methanol/concentrated ammonium hydroxide) to yield 0.31 g ofN-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)methanesulfonamideas an off white solid, mp 190-194° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J=9.1 Hz, 1H), 7.02 (d, J=2.6 Hz,1H), 6.94 (t, J=5.8 Hz, 1H), 6.85 (dd, J=9.1, 2.6 Hz, 1H), 6.52 (s, 2H),5.70 (s, 1H), 5.66 (d, J=7.6 Hz, 1H), 4.93 (s, 2H), 4.72 (br s, 2H),4.04 (t, J=6.3 Hz, 2H), 3.72 (m, 1H), 3.51 (q, J=7.0 Hz, 2H), 2.94 (m,2H), 2.87 (s, 3H), 1.76 (m, 2H), 1.50-1.30 (m, 12H), 1.21 (t, J=7.0 Hz,3H), 1.05 (d, J=6.5 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.8, 157.2, 152.6, 150.1, 147.6, 134.9,125.3, 122.6, 111.4, 109.7, 108.4, 67.5, 65.6, 64.4, 54.2, 51.9, 42.8,40.9, 29.7, 29.0, 26.4, 26.3, 25.6, 23.6, 15.3;

MS (APCI) m/z 592 (M+H)⁺;

Anal. calcd for C₂₈H₄₅N₇O₅S.0.12 H₂O: C, 56.57; H, 7.68; N, 16.49.Found: C, 56.25; H, 8.09; N, 16.37.

Example 372 tert-Butyl2-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate

Part A

Triethylamine (31.88 mL, 228.77 mmol) followed by2,2-dimethyl-1,3-dioxolan-4-methanamine (20.0 g, 152.51 mmol) were addedto a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (48.00 g, 152.51mmol) in dichloromethane (400 mL), which was then stirred at ambienttemperature for 6 hours. The crude reaction mixture was concentratedunder reduced pressure, and the resulting solid was treated with water.The mixture was stirred for 1 hour. The solid was collected byfiltration, washed with water, dried, suspended in diethyl ether (400mL), sonicated, and the resulting precipitate material was collected byfiltration. The product was dried under vacuum at 40° C. for 12 hours toafford 60.1 g of(7-benzyloxy-3-nitro-quinolin4-yl)[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]amineas a yellow solid, mp 154-155° C.

¹H-NMR (300 MHz, CDCl₃) δ 9.74-9.62 (br m, 1H), 9.32 (s, 1H), 8.15 (d,J=9.4 Hz, 1H), 7.51-7.31 (m, 6H), 7.15 (dd, J=9.4, 2.7 Hz, 1H), 5.21 (s,2H), 4.48-4.37 (m, 1H), 4.16-4.05 (m, 2H), 4.04-3.93 (m, 1H), 3.74 (dd,J=8.5, 5.9 Hz, 1H), 1.54 (s, 3H), 1.40 (s, 3H);

MS (APCI) m/z 410.1 (M+H)⁺.

Part B

A solution of sodium dithionate (85% pure, 135.07 g, 659.42 mmol) andpotassium carbonate (101.27 g, 732.73 mmol) in water (450 mL) was addeddropwise to a mechanically stirred mixture of ethyl viologen dibromide(1.1 g, 2.93 mmol) and(7-benzyloxy-3-nitro-quinolin4-yl)[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]amine(60.0 g, 146.54 mmol) in dichloromethane (500 mL) and water (50 mL). Thereaction mixture was stirred at ambient temperature overnight and thendiluted with water (600 mL) and stirred for an additional 10 minutes.The organic phase was separated and the aqueous layer was reextractedwith dichloromethane (400 mL). The combined organic layers were washedwith water (800 mL) and brine (800 mL), dried over sodium sulfate, andconcentrated under reduced pressure to afford 55.60 g of7-benzyloxy-N⁴-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]quinoline-3,4-diamineas a brown foam.

¹H-NMR (300 MHz, CDCl₃) δ 8.38 (s, 1H), 7.83 (d, J=9.3 Hz, 1H),7.51-7.28 (m, 6H), 7.18 (dd, J=9.2, 2.5 Hz, 1H), 5.16 (s, 2H), 4.35 (brs, 1H), 4.30-4.18 (m, 1H), 4.02 (dd, J=8.3, 6.5 Hz, 1H), 3.81 (br s,2H), 3.68 (dd, J=8.3, 6.1 Hz, 1H), 3.60-3.46 (m, 1H), 3.40-3.25 (m, 1H),1.52 (s, 3H), 1.37 (s, 3H);

MS (APCI) m/z 380.0 (M+H)⁺.

Part C

Triethylamine (25.53 mL, 183.17 mmol) was added to a solution of7-benzyloxy-N⁴-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]quinoline-3,4-diamine(55.60 g, 146.54 mmol) in dichloromethane (500 mL) at 0° C. Dropwiseaddition of ethoxyacetyl chloride (22.45 g, 183.17 mmol) to the reactionmixture followed, and the reaction mixture was allowed to stir for 4hours at ambient temperature. The reaction mixture was concentratedunder reduced pressure and the residue was added to a mixture oftriethylamine (61.3 mL, 440 mmol) in ethanol (350 mL) and heated toreflux for 16 hours. The reaction mixture was concentrated under reducedpressure, extracted with dichloromethane (3×300 mL), washed with water(300 mL) and brine (300 mL) and dried over sodium sulfate. The crudematerial was purified by flash column chromatography (silica gel, elutedwith 5% CMA in chloroform) and concentrated under reduced pressure togive 42.5 g of material as a brown solid. The material wasrecrystallized from diethyl ether to afford 37.5 g of7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolineas a white crystalline solid, mp 110-111° C.

¹H-NMR (300 MHz, CDCl₃) δ 9.23 (s, 1H), 8.16 (d, J=9.2 Hz, 1H), 7.75 (d,J=2.7 Hz, 1H), 7.55-7.31 (m, 6H), 5.25 (s, 2H), 5.00 (d, J=12.7 Hz, 1H),4.93-4.75 (m, 3H), 4.72-4.60 (m, 1H), 4.18 (dd, J=8.6, 6.2 Hz, 1H), 3.87(dd, J=8.7, 6.2 Hz, 1H), 3.63 (q, J=7.0 Hz, 2H), 1.45 (s, 3H), 1.29 (s,3H), 1.25 (t, J=7.0 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 157.8, 150.9,146.9, 145.7, 136.5, 135.4, 134.9, 128.7, 128.2, 127.7, 121.2, 118.9,112.4, 111.5, 110.3, 74.7, 70.2, 66.8, 66.4, 65.5, 48.4, 26.6, 25.1,15.0;

MS (APCI) m/z 448.1 (M+H)⁺;

Anal. calcd for C₂₆H₂₉N₃O₄: C, 69.78; H, 6.53; N, 9.39. Found: C, 69.82;H, 6.74; N, 9.34.

Part D

Palladium hydroxide (Pearlman's catalyst) (20% wt. % palladium oncarbon, 2.2 g) was added to a solution of7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline(22.2 g, 49.6 mmol) in acetonitrile (400 mL) and the reaction mixturewas hydrogenated (30 psi, 2.1×10⁵ Pa) for 24 hours on a Parr apparatus.The crude reaction mixture was diluted with 1:1 chloroform/methanol (1L), then was filtered through a layer of CELITE filter agent. Thefiltrate was concentrated under reduced pressure and triturated withacetonitrile. The resulting crystalline material was collected byfiltration, washed with acetonitrile, and dried to afford 16.55 g of1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-olas a white powder, mp 239-240° C.

MS (APCI) m/z 358.1 (M+H)⁺;

Anal. calcd for C₁₉H₂₃N₃O₄: C, 63.85; H, 6.49; N, 11.76. Found: C,63.88; H, 6.78; N, 11.75.

Part E

Using a modification on the procedure described in Part L of Example 2,1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol(8.50 g, 23.8 mmol) was treated with tert-butyl 2-iodoethylcarbamate(7.10 g, 26.2 mmol) and cesium carbonate (11.62 g, 35.67 mmol) in DMF(120 mL). During the workup, after the reaction mixture was concentratedunder reduced pressure, the residue was treated with water (75 mL) andstirred for 30 minutes. A precipitate was isolated by filtration andwashed with diethyl ether to yield 8.7 g of tert-butyl2-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas an off-white solid, mp 152-153° C.

MS (ESI) m/z 501.3 (M+H)⁺;

Anal. calcd for C₂₆H₃₆N₄O₆: C, 62.38; H, 7.25; N, 11.19. Found: C,62.33; H, 7.45; N, 11.08.

Part F

mCPBA (75% pure, 7.6 g, 34 mmol) was added to a stirred solution oftert-butyl2-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(8.5 g, 17 mmol) in dichloromethane (100 mL) at room temperature. Thereaction mixture was stirred for 4 hours, then was diluted withdichloromethane (50 mL), washed with 4% aqueous sodium carbonate (2×75mL), brine (100 mL), and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (100 mL) and concentratedammonium hydroxide (50 mL) was added. The mixture was cooled to 0° C.and p-toluenesulfonyl chloride (4.04 g, 21.2 mmol) was added inportions. The reaction mixture was allowed to warm to room temperatureand was stirred for 16 hours, then was diluted with dichloromethane (200mL) and washed with 2 M aqueous sodium carbonate (2×150 mL). The aqueouslayer was back-extracted with dichloromethane (100 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated. The solid was triturated with diethyl etherand isolated by filtration to yield 3.55 g of tert-butyl2-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas a white powder, mp 82-84° C.

MS (APCI) m/z 516.3 (M+H)⁺;

Anal. calcd for C₂₆H₃₇N₅O₆: C, 60.57; H, 7.23; N, 13.58. Found: C,60.28; H, 7.55; N, 13.45.

Example 3733-[4-Amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride

A suspension of tert-butyl2-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(prepared in Example 372, 1.5 g, 2.9 mmol) in ethanol (20 mL) and 4.3 MHCl in ethanol (2.70 mL, 17.5 mmol) was heated at reflux overnight. Thereaction mixture was allowed to cool to room temperature and a whitesolid was collected by filtration, washed with ethanol, and dried undervacuum at 60° C. to yield 0.85 g of7-(2-aminoethoxy)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride as a white solid, mp 221-223° C.

MS (APCI) m/z 376.1 (M+H)⁺;

Anal. calcd for C₂₆H₃₇N₅O₆.2.2HCl.0.5H₂O: C, 46.17; H, 6.09; N, 14.95.Found: C, 46.48; H, 6.13; N, 14.97.

Example 374 tert-Butyl4-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate

Part A

A solution of diisopropyldiazodicarboxylate (0.710 g, 3.50 mmol) intetrahydrofuran (6 mL) was added dropwise to a mixture of1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol(prepared as described in Parts A-D of Example 372, 1.00 g, 2.80 mmol),tert-butyl 4-hydroxypiperidine-1-carboxylate (0.70 g, 3.50 mmol), andtriphenylphosphine (0.920 g, 3.50 mmol) in tetrahydrofuran (35 mL) at 0°C. The resulting solution was allowed to warm to room temperature over16 hours. The solution was concentrated under reduced pressure. Thecrude product was purified by chromatography (silica gel, gradientelution with 0-50% CMA in chloroform) to provide 1.16 g of tert-butyl4-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas a white foam.

MS (ESI) m/z 541.4 (M+H)⁺.

Part B

Using the method described in Part F of Example 372, tert-butyl4-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(12.66 g, 23.42 mmol) was converted into 7.04 g of tert-butyl4-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate,which was isolated as a white solid, mp 158-159° C.

MS (ESI) m/z 556.6 (M+H)⁺;

Anal. calcd for C₂₉H₄₁N₅O₆: C, 62.68; H, 7.44; N, 12.60. Found: C,62.29; H, 7.40; N, 12.37.

Example 3753-[4-Amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride

Using the method described in Example 373, tert-butyl4-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(7.00 g, 12.6 mmol) was converted into 5.22 g of3-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride, which was isolated as a tan powder, mp 278-280° C.

MS (ESI) m/z 416.2 (M+H)⁺;

Anal. calcd for C₂₁H₂₉N₅O₄.2HCl: C, 51.64; H, 6.40; N, 14.34; Cl, 14.52.Found: C, 51.48; H, 6.38; N, 14.13; Cl, 14.49.

Examples 376-386

A reagent (0.10 mmol, 1.1 equivalents) from the table below was added toa test tube containing a solution of3-[4-amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride (43 mg, 0.09 mmol, prepared as described in Example 373)and N,N-diisopropylethylamine (0.051 mL, 0.29 mmol) inN,N-dimethylacetamide (1 mL). The test tubes were capped and shaken for8 hours at room temperature and then two drops of water were added toeach test tube. The solvent was removed by vacuum centrifugation. Thecompounds were purified by preparative high performance liquidchromatography (prep HPLC) using a Waters FractionLynx automatedpurification system. The prep HPLC fractions were analyzed using aWaters LC/TOF-MS, and the appropriate fractions were centrifugeevaporated to provide the trifluoroacetate salt of the desired compound.Reversed phase preparative liquid chromatography was performed withnon-linear gradient elution from 5-95% B where A is 0.05%trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile. Fractions were collected by mass-selectivetriggering. The table below shows the reagent added to each test tube,the structure of the resulting compound, and the observed accurate massfor the isolated trifluoroacetate salt.

Examples 376-386

Measured Ex- Mass ample Reagent R (M + H) 376 Methyl isocyanate

433.2225 377 Isopropyl isocyanate

461.2533 378 n-Butyl isocyanate

475.2686 379 Cyclopentyl isocyanate

487.2704 380 Phenyl isocyanate

495.2371 381 Benzyl isocyanate

509.2525 382 Benzoyl isocyanate

523.2297 383 3-Methoxyphenyl isocyanate

525.2471 384 3-Chlorophenyl isocyanate

529.1983 385 trans-2- Phenyl- cyclopropyl isocyanate

535.2686 386 2-Morpholino- ethyl isothiocyanate

548.2625

Example 387 tert-Butyl4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate

Part A

A modification on the methods described in Parts A-H of Example 2 wereused to prepare2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol, with3-benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of4-benzyloxyaniline and ethoxyacetyl chloride, respectively. A solutionof diisopropyl azodicarboxylate (6.28 mL, 31.9 mmol) in tetrahydrofuran(25.5 mL) was added dropwise to a mixture of2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (7.28 g, 25.5mmol), triphenylphosphine (8.36 g, 31.9 mmol), and t-butyl4-hydroxypiperidine-1-carboxylate (6.42 g, 31.9 mmol) in tetrahydrofuran(191 mL) at 5° C. The mixture was allowed to warm to room temperature.After 2 days, the solvent was removed under reduced pressure and theresidue was purified by flash chromatography (silica gel, gradientelution with 1.5-4% methanol in dichloromethane) to yield 9.77 g oftert-butyl4-{[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas a gray amorphous solid.

Part B

A stirred solution of tert-butyl4-{[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(9.77 g, 20.8 mmol) in chloroform (175 mL) at room temperature wastreated with mCPBA (55% pure, 6.54 g, 20.8 mmol). After 45 minutes,concentrated ammonium hydroxide (175 mL) was added, followed byp-toluenesulfonyl chloride (3.97 g, 20.8 mmol). The mixture was stirredfor 62 hours, then the layers were separated and the aqueous layer wasextracted with chloroform. The combined organic layers were washed withwater and saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel, gradientelution with 1.5-12.5% CMA in chloroform) followed by recrystallizationfrom acetonitrile to afford 6.3 g of tert-butyl4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas tan crystals, mp 173-175° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=9.1 Hz, 1H), 7.10 (d, J=2.4 Hz,1H), 6.93 (dd, J=9.0, 2.6 Hz, 1H), 6.39 (s, 2H), 4.70-4.61 (m, 1H),4.46-4.41 (m, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.75-3.67 (m, 2H), 3.29 (s,3H), 3.26-3.12 (m, 4H), 2.02-1.91 (m, 2H), 1.87-1.75 (m, 2H), 1.64-1.51(m, 2H), 1.41 (s, 9H), 0.97 (t, J=7.3 Hz, 3H);

MS (ESI) m/z 484.2923 (484.2924 calcd for C₂₆H₃₇N₅O₄, M+H⁺).

Anal. calcd for C₂₆H₃₇N₅O₄.0.75H₂O: C, 62.82; H, 7.81; N, 14.09. Found:C, 62.48; H, 8.16; N, 14.01.

Example 3884-{[4-Amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamide

Part A

tert-Butyl4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(prepared as described in Example 387, 2.11 g, 4.36 mmol) was treatedwith concentrated hydrochloric acid (3 mL). After vigorous bubbling, asolution formed. The solution was diluted with ethanol (50 mL) andevaporated (3×). The resulting oil was dissolved in brine (15 mL) andwater (5 mL) and made basic with 50% aqueous sodium hydroxide(approximately 1.5 mL). The aqueous layer was extracted withdichloromethane (3×). The organic layers were combined, washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to provide 1.7 g of2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamineas a white solid.

Part B

Isopropyl isocyanate (0.256 mL, 2.61 mmol) was added dropwise to astirred mixture of2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(1.00 g, 2.61 mmol) in chloroform at 0° C. The reaction mixture wasallowed to warm to room temperature and was stirred for 16 hours. Thesolvent was evaporated under reduced pressure. The crude product waspurified by flash chromatography (silica gel, gradient elution with4-12% CMA in chloroform) followed by recrystallization from acetonitrileto afford 0.530 g of4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamideas white crystals, mp 176-179° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=9.1 Hz, 1H), 7.08 (d, J=2.5 Hz,1H), 6.91 (dd, J=9.0, 2.6 Hz, 1H), 6.36 (s, 2H), 6.17 (d, J=7.4 Hz, 1H),4.66-4.56 (m, 1H), 4.47-4.37 (m, 2H), 3.80 (t, J=6.7 Hz, 2H), 3.77-3.66(m, 3H), 3.28 (s, 3H), 3.17-3.04 (m, 4H), 2.00-1.87 (m, 2H), 1.86-1.72(m, 2H), 1.58-1.44 (m, 2H), 1.05 (d, J=6.6 Hz, 6H), 0.96 (t, J=7.3 Hz,3H);

MS (ESI) m/z 469.2912 (469.2927 calcd for C₂₅H₃₆N₆O₃, M+H⁺).

Anal. calcd for C₂₅H₃₆N₆O₃: C, 64.08; H, 7.74; N, 17.93. Found: C,63.73; H, 7.73; N, 17.76.

Example 3897-[(1-Isobutyrylpiperidin-4-yl)oxy]-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Isobutyryl chloride (0.273 mL, 2.61 mmol) was added dropwise to astirred solution of2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(prepared as described in Part A of Example 388, 1.00 g, 2.61 mmol) inchloroform at 0° C. After 2 hours, the solution was allowed to warm toambient temperature for 1 hour. Saturated aqueous sodium carbonate (15mL) and water (10 mL) were added and the mixture was allowed to stir for16 hours. The mixture was transferred to a separatory funnel, the layerswere separated, and the aqueous layer was extracted with dichloromethane(2×30 mL). The organic layers were combined, washed with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. Recrystallizationfrom acetonitrile afforded 1.00 g of7-[(1-isobutyrylpiperidin-4-yl)oxy]-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a flocculent white solid, mp 165-166° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=9.1 Hz, 1H), 7.11 (d, J=2.6 Hz,1H), 6.92 (dd, J=9.0, 2.6 Hz, 1H), 6.37 (s, 2H), 4.75-4.65 (m, 1H),4.47-4.37 (m, 2H), 3.98-3.85 (m, 1H), 3.85-3.77 (m, 1H), 3.80 (t, J=6.8Hz, 2H), 3.47-3.34 (m, 1H), 3.28 (s, 3H), 3.30-3.19 (m, 1H), 3.15 (t,J=6.8 Hz, 2H), 2.94-2.84 (m, 1H), 2.06-1.89 (m, 2H), 1.86-1.72 (m, 2H),1.69-1.46 (m, 2H), 1.00 (d, J=6.7 Hz, 6H), 0.96 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 454.2810 (454.2818 calcd for C₂₅H₃₅N₅O₃, M+H⁺).

Anal. calcd for C₂₅H₃₃N₅O₃: C, 66.20; H, 7.78; N, 15.44. Found: C,65.95; H, 8.09; N, 15.43.

Example 3902-(2-Methoxyethyl)-7-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Using the method described in Example 389,2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(1.00 g, 2.61 mmol) was converted into2-(2-methoxyethyl)-7-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine,using methanesulfonyl chloride (0.202 mL, 2.61 mmol) in lieu ofisobutyryl chloride. The crude product was purified by flashchromatography (silica gel, eluting with a step gradient of CMA inchloroform (4-12% CMA increasing by 2% CMA every 500 mL) followed bytrituration with acetonitrile to afford 1.1 g of2-(2-methoxyethyl)-7-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 224-225.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=9.0 Hz, 1H), 7.12 (d, J=2.6 Hz,1H), 6.95 (dd, J=9.0, 2.6 Hz, 1H), 6.39 (s, 2H), 4.70-4.62 (m, 1H),4.46-4.41 (m, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.44-3.34 (m, 2H), 3.29 (s,3H), 3.19-3.12 (m, 4H), 2.92 (s, 3H), 2.12-2.00 (m, 2H), 1.87-1.73 (m,4H), 0.97 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 462.2184 (462.2175 calcd for C₂₂H₃₁N₅O₄S, M+H⁺).

Anal. calcd for C₂₂H₃₁N₅O₄S.0.10CH₂Cl₂: C, 56.47; H, 6.69; N, 14.90; S,6.82. Found: C, 56.36; H, 6.93; N, 14.80; S, 6.96.

Example 3914-{[4-Amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxamide

Trimethylsilylisocyanate (0.225 mL, 1.67 mmol) was added dropwise to aslurry of2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(prepared as described in Part A of Example 388, 0.640 g, 1.67 mmol) inchloroform (16 mL) at 0° C. The reaction mixture was stirred for 40minutes and water (10 mL) was added. The reaction mixture was stirredvigorously for 2 hours, diluted with 200 mL ethanol, and thenconcentrated under reduced pressure to approximately 100 mL. Another 100mL ethanol was added and the solution was evaporated to afford a whitesolid that was recrystallized from ethanol to provide 0.625 g of4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxamideas granular off-white crystals, mp 207-208.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=9.0 Hz, 1H), 7.09 (d, J=2.5 Hz,1H), 6.92 (dd, J=9.0, 2.5 Hz, 1H), 6.37 (s, 2H), 5.94 (s, 2H), 4.66-4.58(m, 1H), 4.44-4.39 (m, 2H), 3.80 (t, J=6.7 Hz, 2H), 3.75-3.63 (m, 2H),3.28 (s, 3H), 3.17-3.04 (m, 4H), 1.99-1.87 (m, 2H), 1.86-1.71 (m, 2H),1.60-1.44 (m, 2H), 0.96 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 158.0, 155.5, 151.9, 149.8, 146.5, 132.6,125.1, 121.1, 112.5, 109.9, 109.0, 72.2, 70.2, 58.1, 46.1, 40.9, 30.6,27.1, 23.0, 10.6;

MS (ESI) m/z 427.2443 (427.2458 calcd for C₂₂H₃₀N₆O₃, M+H⁺).

Anal. calcd for C₂₂H₃₀N₆O₃.0.50H₂O: C, 60.67; H, 7.17; N, 19.30. Found:C, 61.03; H, 7.60; N, 19.61.

Example 3922-(2-Methoxyethyl)-7-[3-(methylsulfonyl)propoxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

A modification on the methods described in Parts A-H of Example 2 wereused to prepare2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol, with3-benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of4-benzyloxyaniline and ethoxyacetyl chloride, respectively. Diisopropylazodicarboxylate (2.07 mL, 10.5 mmol) was added dropwise to a slurry of2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (2.00 g, 7.01mmol), triphenylphosphine (2.75 g, 10.5 mmol), and3-(methylthio)propan-1-ol (1.08 mL, 10.5 mmol) in tetrahydrofuran (70mL) at 0° C. The solution was stirred for 30 minutes at 0° C., then atroom temperature for 16 hours. The solvent was removed under reducedpressure and the residue was dissolved in ethyl acetate, treated with 1M hydrochloric acid (40 mL), and stirred for 30 minutes. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×25mL). The aqueous layer was adjusted to approximately pH 14 with 50%aqueous sodium hydroxide and then was extracted with dichloromethane(3×50 mL). The organic layers were combined, washed with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by flash chromatography (silica gel, gradient elution with 1-4%methanol in dichloromethane) to provide 2.0 g of2-(2-methoxyethyl)-7-[3-(methylthio)propoxy]-1-propyl-1H-imidazo[4,5-c]quinolineas an opaque solid.

Part B

3-Chloroperoxybenzoic acid (4.63 g, 16.1 mmol) was added to a solutionof2-(2-methoxyethyl)-7-[3-(methylthio)propoxy]-1-propyl-1H-imidazo[4,5-c]quinoline(2.0 g, 5.35 mmol) in chloroform (45 mL). After 1 hour, concentratedammonium hydroxide (45 mL) was added and the mixture was stirred for 30minutes. p-Toluenesulfonyl chloride (1.07 g, 5.62 mmol) was added in twoportions. After the mixture was allowed to stir for 16 hours, the layerswere separated and the aqueous layer was extracted with dichloromethane.The combined organic layers were washed with 14% aqueous ammoniumhydroxide, water, and brine. The organic layer was dried over anhydroussodium sulfate, filtered, and evaporated. The resulting oil wascrystallized from hot acetonitrile to afford a tan solid that wasisolated by filtration. The solid was subjected to flash columnchromatography (silica gel, gradient elution with 2-14% CMA inchloroform) followed by recrystallization from acetonitrile to yield0.510 g of2-(2-methoxyethyl)-7-[3-(methylsulfonyl)propoxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas red-violet crystals, mp 170-171° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.91 (d, J=9.0 Hz, 1H), 7.07 (d, J=2.6 Hz,1H), 6.92 (dd, J=9.0, 2.6 Hz, 1H), 6.40 (s, 2H), 4.46-4.41 (m, 2H), 4.18(t, J=6.2 Hz, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.34-3.29 (m, 2H), 3.29 (s,3H), 3.16 (t, J=6.8 Hz, 2H), 3.03 (s, 3H), 2.27-2.14 (m, 2H), 1.87-1.75(m, 2H), 0.97 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 421.1903 (421.1910 calcd for C₂₀H₂₈N₄O₄S, M+H⁺).

Anal. calcd for C₂₀H₂₈N₄O₄S: C, 57.12; H, 6.71; N, 13.32; S, 7.62.Found: C, 57.16; H, 6.70; N, 13.46; S, 7.74.

Example 393 tert-Butyl3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate

Part A

A modification on the methods described in Parts A-H of Example 2 wereused to prepare2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol, with3-benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of4-benzyloxyaniline and ethoxyacetyl chloride, respectively.2-(2-Methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (20.0 g, 70mmol) was converted into tert-butyl{3-[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}carbamateusing a modification of the method described in Part C of Example 7. Thereaction was worked up by removing the solvent under reduced pressure.The residue was partitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate. The organic layers werecombined, washed with water (2×500 mL) and brine, dried over anhydrousmagnesium sulfate, filtered, and evaporated under reduced pressure toyield tert-butyl{3-[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}carbamateas a brown oil, which was used without further purification.

Part B

The material from Part A was dissolved in chloroform (700 mL) andtreated with mCPBA (60% pure, 21.96 g, 75 mmol). After 1 hour, thereaction mixture was poured into 2% aqueous sodium carbonate. The layerswere separated and the organic layer was washed with water and saturatedaqueous sodium chloride. The organic layer was dried over anhydrousmagnesium sulfate, filtered and evaporated. The crude product waspurified by flash chromatography (silica gel, gradient elution with 2-7%methanol in dichloromethane) to afford 19.3 g of tert-butyl3-{[2-(2-methoxyethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamateas a tan foam.

Part C

p-Toluenesulfonyl chloride (8.0 g, 42 mmol) was added over ten minutesto a stirred mixture of tert-butyl3-{[2-(2-methoxyethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate(19.3 g, 42.0 mmol) in dichloromethane (300 mL) and concentratedammonium hydroxide (300 mL) at 7° C. The mixture was allowed to stir for20 minutes, then the cooling bath was removed and the mixture wasallowed to stir at ambient temperature for 2 hours. The layers wereseparated and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, washed with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andevaporated under reduced pressure. Recrystallization from acetonitrileafforded 12.0 g of tert-butyl3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamateas flocculent white crystals, mp 133.5-135° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=9.0 Hz, 1H), 7.05 (d, J=2.7 Hz,1H), 6.95-6.87 (m, 1H), 6.89 (dd, J=9.0, 2.7 Hz, 1H), 6.37 (s, 2H),4.46-4.41 (m, 2H), 4.05 (t, J=6.2 Hz, 2H), 3.81 (t, J=6.8 Hz, 2H), 3.29(s, 3H), 3.18-3.08 (m, 4H), 1.91-1.74 (m, 4H), 1.38 (s, 9H), 0.97 (t,J=7.3 Hz, 3H);

MS (ESI) m/z 458.2758 (458.2767 calcd for C₂₄H₃₅N₅O₄, M+H⁺).

Anal. calcd for C₂₄H₃₅N₅O₄.0.73H₂O: C, 61.24; H, 7.81; N, 14.88. Found:C, 61.23; H, 7.62; N, 14.78.

Example 3947-(3-Aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Concentrated hydrochloric acid (8.5 mL) was added to a solution oftert-butyl3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate(prepared as described in Example 393, 12 g, 26 mmol) in ethanol (300mL). The solution was heated at reflux for 4 hours. Upon cooling toambient temperature a precipitate formed. The solid was isolated byfiltration and the filtrate was evaporated to afford a white solid. Thesolids were combined and dissolved in water (40 mL). The solution wasadjusted to approximately pH 12 with 50% aqueous sodium hydroxide andthen was extracted with dichloromethane (4×250 mL). The organic layerswere combined, washed with water and saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered, and evaporated toyield a solid that was purified by trituration in hot acetonitrile toprovide 6.5 g of7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas yellow crystals, mp 165-166.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=9.0 Hz, 1H), 7.06 (d, J=2.6 Hz,1H), 6.89 (dd, J=9.1, 2.6 Hz, 1H), 6.37 (s, 2H), 4.46-4.41 (m, 2H), 4.10(t, J=6.4 Hz, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.29 (s, 3H), 3.16 (t, J=6.7Hz, 2H), 2.72 (t, J=6.7 Hz, 2H), 1.87-1.74 (m, 4H), 1.47 (br s, 2H),0.97 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 358.2231 (358.2243 calcd for C₁₉H₂₇N₅O₂, M+H⁺).

Anal. calcd for C₁₉H₂₇N₅O₂: C, 63.84; H, 7.61; N, 19.59. Found: C,63.50; H, 7.75; N, 19.46.

Example 395N-(3-{[4-Amino-2-(2-hydroxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamide

Part A

Isobutyryl chloride (0.375 mL, 3.58 mmol) was added dropwise to a slurryof7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(prepared as described in Example 394, 1.28 g, 3.58 mmol) indichloromethane (22 mL) at 0° C. The reaction mixture was allowed tostir for 30 minutes at 0° C., then the reaction mixture was allowed tostir for 16 hours at ambient temperature. Saturated aqueous sodiumcarbonate was added and the reaction mixture was stirred for 1 hour,resulting in the formation of a flocculent solid. The solid was isolatedby filtration and dissolved in dichloromethane. The dichloromethane waswashed with water and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The resulting white solid was recrystallized from acetonitrileto afford 1.14 g ofN-(3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamideas an off-white solid.

Part B

A 1.0 M solution of boron tribromide in dichloromethane (2.55 mL, 2.55mmol) was added over 1 minute to a slurry ofN-(3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamide(1.09 g, 2.55 mmol) at 0° C. The clumpy slurry was allowed to stir for15 minutes at 0° C., then was allowed to stir for another hour atambient temperature. Additional boron tribromide solution (0.6 mL, 0.6mmol) was added. After 16 hours, the reaction was quenched with 6 Mhydrochloric acid (10 mL), stirred until all the solids dissolved, andthe dichloromethane was removed under reduced pressure. The aqueouslayer was adjusted to approximately pH 13 with 50% aqueous sodiumhydroxide and was extracted with ethyl acetate. The organic layer waswashed with water and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, filtered, and evaporated. The material waspurified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 2-22% CMA in chloroform) followed by triturationwith acetonitrile to afford 0.325 g ofN-(3-{[4-amino-2-(2-hydroxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamideas a white solid, mp 190.5-192° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=9.1 Hz, 1H), 7.81 (t, J=5.5 Hz,1H), 7.05 (d, J=2.6 Hz, 1H), 6.90 (dd, J=9.0, 2.6 Hz, 1H), 6.43 (s, 2H),4.88 (t, J=5.5 Hz, 1H), 4.47-4.42 (m, 2H), 4.06 (t, J=6.3 Hz, 2H),3.90-3.84 (m, 2H), 3.26-3.20 (m, 2H), 3.06 (t, J=6.6 Hz, 2H), 2.42-2.28(m, 1H), 1.93-1.75 (m, 4H), 1.00 (d, J=6.9 Hz, 6H), 0.98 (t, J=7.3 Hz,3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 176.0, 157.2, 151.9, 150.5, 146.5, 132.6,125.0, 120.9, 111.6, 108.9, 108.1, 65.1, 59.6, 46.0, 35.4, 34.0, 30.2,28.9, 22.9, 19.5, 10.6;

MS (ESI) m/z 414.3 (M+H)⁺;

Anal. calcd for C₂₂H₃₁N₅O₃: C, 63.90; H, 7.56; N, 16.94. Found: C,63.76; H, 7.78; N, 16.92.

Example 396N-(3-{[4-Amino-2-(2-hydroxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)nicotinamide

Using the procedures described in Parts A and B of Example 395, withnicotinoyl chloride hydrochloride (0.627 g, 3.52 mmol) used in lieu ofisobutyryl chloride,7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(prepared as described in Example 394, 1.28 g, 3.58 mmol) was convertedinto 0.230 g ofN-(3-{[4-amino-2-(2-hydroxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)nicotinamideafter recrystallization from acetonitrile to yield pale yellow needles,mp 183.5-184.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (dd, J=2.4, 0.7 Hz, 1H), 8.77 (t, J=5.4Hz, 1H), 8.70 (dd, J=4.7, 1.7 Hz, 1H), 8.21-8.17 (m, 1H), 7.90 (d, J=9.1Hz, 1H), 7.52-7.48 (m, 1H), 7.08 (d, J=2.6 Hz, 1H), 6.91 (dd, J=9.0, 2.6Hz, 1H), 6.41 (s, 2H), 4.88 (t, J=5.6 Hz, 1H), 4.47-4.42 (m, 2H), 4.14(t, J=6.2 Hz, 2H), 3.90-3.84 (m, 2H), 3.52-3.46 (m, 2H), 3.06 (t, J=6.6Hz, 2H), 2.09-2.00 (m, 2H), 1.88-1.75 (m, 2H), 0.98 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.2, 151.9, 151.7, 150.5, 148.3, 146.5,134.8, 132.6, 130.0, 125.0, 123.3, 120.9, 111.6, 108.9, 108.2, 65.2,59.6, 46.0, 36.4, 30.2, 28.8, 22.9, 10.6;

MS (ESI) m/z 449.3 (M+H)⁺;

Anal. calcd for C₂₄H₂₈N₆O₃: C, 64.27; H, 6.29; N, 18.74. Found: C,63.99; H, 6.53; N, 18.87.

Example 397 tert-Butyl4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamate

Part A

Using a modification on the procedure described in Part E of Example 2,tert-butyl 4-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}butylcarbamatewas synthesized using 7-benzyloxy-3-nitroquinolin-4-ol (prepared asdescribed in Steps A-C of Example 1) and tert-butyl4-aminobutylcarbamate in lieu of the 6-benzyloxy-3-nitroquinolin-4-oland propylamine, respectively.

Part B

A mixture of tert-butyl4-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}butylcarbamate (30.0 g,64.3 mmol) and 5% platinum on carbon (3.0 g) in toluene (675 mL) and2-propanol (100 mL) was hydrogenated on a Parr apparatus for 12.5 hoursat 24 psi (1.7×10⁵ Pa). The mixture was filtered through CELITE filteragent, which was rinsed afterwards with 1:1 toluene/2-propanol and2-propanol. The combined filtrates were concentrated under reducedpressure to afford 28 g of tert-butyl4-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}butylcarbamate as a viscousblack oil that was used in the next step without purification.

Part C

Ethoxyacetyl chloride (7.87 mL, 64.3 mmol) was added dropwise to astirred solution of the material from Part B in dichloromethane (319mL). After 1 hour, the solution was concentrated under reduced pressure.The residue was dissolved in ethanol (319 mL) and triethylamine (35.84mL, 257 mmol) and the solution was heated at reflux for 4 hours, thenwas allowed to cool to room temperature and was concentrated underreduced pressure. The residue was dissolved in dichloromethane andwashed with water and saturated aqueous sodium chloride. The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting semi-solid wasdissolved in hot acetonitrile and allowed to cool. Evaporation of theacetonitrile under reduced pressure afforded 30 g of tert-butyl4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamateas a chunky brown solid.

Part D

A mixture of tert-butyl4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate(15 g, 29.7 mmol) and 10% palladium on carbon (4.5 g, wetted withethanol) in 1:1 ethanol/methanol (400 mL) was hydrogenated using a Parrapparatus at 28 psi (1.9×10⁵ Pa) for 16 hours. The mixture was filteredthrough CELITE filter agent, which was subsequently washed withmethanol. The filtrate was concentrated under reduced pressure toafforded 10.8 g of tert-butyl4-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamateas a green-yellow solid.

Part E

Using the conditions described in Part A of Example 392, tert-butyl4-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate(3.50 g, 8.44 mmol) was converted into tert-butyl4-{2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamateusing 1-(3-hydroxypropyl)pyrrolidin-2-one (1.64 mL, 12.7 mmol) in lieuof 3-(methylthio)propan-1-ol. The reaction was worked up by removing thesolvent under reduced pressure. The residue was subjected to flashchromatography (silica gel, elution with ethyl acetate followed bygradient elution with 1-5% methanol in dichloromethane) to yield 3.79 gof tert-butyl4-{2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamateas a viscous yellow oil.

Part F

Using a modification on the procedure described in Part B of Example392, tert-butyl4-{2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamate(3.79 g, 7.02 mmol) was converted into tert-butyl4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamate.After the p-toluenesulfonyl chloride was added, the mixture was allowedto stir for 72 hours. The layers were separated and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,washed with 5% aqueous sodium bicarbonate, water, and saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered, andevaporated. Recrystallization from acetonitrile afforded 3.1 g oftert-butyl4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamateas a white solid, mp 134.5-136° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=9.0 Hz, 1H), 7.04 (d, J=2.5 Hz,1H), 6.90 (dd, J=8.8, 2.3 Hz, 1H), 6.81 (t, J=5.0 Hz, 1H), 6.51 (s, 2H),4.74 (s, 2H), 4.52-4.47 (m, 2H), 4.04 (t, J=6.2 Hz, 2H), 3.55 (q, J=7.0Hz, 2H), 3.42-3.34 (m, 4H), 2.99-2.93 (m, 2H), 2.22 (t, J=8.0 Hz, 2H),2.00-1.88 (m, 4H), 1.87-1.74 (m, 2H), 1.61-1.50 (m, 2H), 1.33 (s, 9H),1.16 (t, J=7.0 Hz, 3H);

MS (ESI) m/z 555.3287 (555.3295 calcd for C₂₉H₄₂N₆O₅, M+H⁺).

Anal. calcd for C₂₉H₄₂N₆O₅.1.25H₂O: C, 60.35; H, 7.77; N, 14.56. Found:C, 60.35; H, 7.83; N, 14.12.

Example 3981-(3-{[4-Amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-onedihydrochloride

A solution of tert-butyl4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamate(prepared as described in Example 397, 2.90 g, 5.23 mmol) in 4 Methanolic hydrogen chloride was heated at reflux for 2 hours. Thesolution was allowed to cool to room temperature and a precipitateformed that was isolated by filtration to afford 2.52 g of1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-onedihydrochloride as a white powder, mp>250° C. ¹H NMR (300 MHz, DMSO-d₆)δ 13.92 (s, 1H), 9.30-8.40 (br s, 2H), 8.15 (d, J=9.2 Hz, 1H), 8.13-8.00(m, 3H), 7.30 (d, J=2.5 Hz, 1H), 7.20 (dd, J=9.1, 2.4 Hz, 1H), 4.83 (s,2H), 4.65-4.60 (m, 2H), 4.10 (t, J=6.1 Hz, 2H), 3.60 (q, J=7.0 Hz, 2H),3.41-3.37 (m, 4H), 2.87-2.76 (m, 2H), 2.22 (t, J=8.0 Hz, 2H), 2.04-1.85(m, 6H), 1.81-1.70 (m, 2H), 1.19 (t, J=7.0 Hz, 3H);

MS (ESI) m/z 455.2784 (455.2771 calcd for C₂₄H₃₄N₆O₃, M+H⁺).

Anal. calcd for C₂₄H₃₄N₆O₃.1.60H₂O.2.15HCl: C, 51.28; H, 7.06; N, 14.95;Cl, 13.59.

Found: C, 51.29; H, 7.36; N, 14.93; Cl, 13.48.

Example 399N-(4-{4-Amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)-N′-isopropylurea

Isopropyl isocyanate (0.187 mL, 1.90 mmol) was added dropwise to astirred solution of1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-onedihydrochloride (prepared as described in Example 398, 1.0 g, 1.90 mmol)and triethylamine (0.530 mL, 3.80 mmol) in dichloromethane (20 mL) atroom temperature. After 1.5 hours, the solvent was removed under reducedpressure and the residue was purified by flash chromatography (silicagel, gradient elution with 2-12% CMA in chloroform) followed byrecrystallization from acetonitrile to yield 0.730 g ofN-(4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)-N′-isopropylureaas an opaque solid, mp 98-101° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=9.0 Hz, 1H), 7.05 (d, J=2.6 Hz,1H), 6.91 (dd, J=9.0, 2.6 Hz, 1H), 6.55 (s, 2H), 5.69 (t, J=5.7 Hz, 1H),5.57 (d, J=7.7 Hz, 1H), 4.74 (s, 2H), 4.53-4.48 (m, 2H), 4.04 (t, J=6.3Hz, 2H), 3.69-3.58 (m, 1H), 3.55 (q, J=7.0 Hz, 2H), 3.40-3.34 (m, 4H),3.03 (q, J=6.3 Hz, 2H), 2.22 (t, J=8.0 Hz, 2H), 2.00-1.88 (m, 4H),1.88-1.76 (m, 2H), 1.58-1.48 (m, 2H), 1.16 (t, J=7.0 Hz, 3H), 0.98 (d,J=6.5 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 173.9, 157.5, 157.4, 152.2, 148.0, 146.8,133.4, 124.8, 121.4, 111.7, 108.7, 108.0, 65.3, 64.2, 46.5, 45.1, 40.8,39.1, 30.4, 27.3, 26.7, 23.2, 17.5, 14.9;

MS (ESI) m/z 540.3315 (540.3298 calcd for C₂₈H₄₁N₇O₄, M+H⁺).

Anal. calcd for C₂₈H₄₁N₇O₄: C, 62.32; H, 7.66; N, 18.17. Found: C,61.95; H, 7.90; N, 18.46.

Example 400N-(4-{4-Amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)methanesulfonamide

Using the procedure described in Example 399,1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-onedihydrochloride (prepared as described in Example 398, 1.0 g, 1.90 mmol)was converted intoN-(4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)methanesulfonamideusing methanesulfonyl chloride (0.147 mL, 1.90 mmol) in lieu ofisopropyl isocyanate. Recrystallization from acetonitrile afforded 0.246g ofN-(4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)methanesulfonamideas white crystals, mp 157° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (d, J=9.0 Hz, 1H), 7.06 (d, J=2.6 Hz,1H), 6.99 (dd, J=9.0, 2.6 Hz, 1H), 6.93 (dd, J=9.0, 2.6 Hz, 1H), 6.65(s, 2H), 4.75 (s, 2H), 4.55-4.50 (m, 2H), 4.04 (t, J=6.2 Hz, 2H), 3.56(q, J=7.0 Hz, 2H), 3.40-3.34 (m, 4H), 2.99 (q, J=6.3 Hz, 2H), 2.87 (s,3H), 2.22 (t, J=8.0 Hz, 2H), 2.00-1.83 (m, 6H), 1.69-1.59 (m, 2H), 1.17(t, J=7.0 Hz, 3H);

MS (ESI) m/z 533.2565 (533.2546 calcd for C₂₅H₃₆N₆O₅S, M+H⁺).

Anal. calcd for C₂₅H₃₆N₆O₅S: C, 56.37; H, 6.81; N, 15.78; S, 6.02.Found: C, 56.08; H, 6.74; N, 15.47; S, 6.31.

Example 4011-[4-(1,1-Dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

A solution of tert-butyl4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate(prepared as described in Parts A-C of Example 397, 21.0 g, 41.6 mmol)and concentrated hydrochloric acid (13 mL) in ethanol (100 mL) washeated at reflux for 1 hour. The solution was allowed to cool to roomtemperature and a precipitate formed that was isolated by filtration toyield 12.10 g of4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-aminedihydrochloride as a light brown solid.

Part B

3-Chloropropanesulfonyl chloride (4.58 mL, 37.7 mmol) was added dropwiseto a solution of4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-aminedihydrochloride (12.1 g, 25.3 mmol) and triethylamine (14.0 mL, 101mmol) in dichloromethane (168 mL) at room temperature. The solution wasstirred for 17 hours, then transferred to a separatory funnel and washedwith 5% aqueous sodium carbonate, water, and saturated aqueous sodiumchloride. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue wasdissolved in DMF (168 mL) and treated with1,8-diazabicyclo[5.4.0]undec-7-ene (5.70 mL, 38 mmol). The solution wasstirred for 40 hours, then the DMF was removed under reduced pressure.The residue was dissolved in dichloromethane and washed repeatedly withwater then saturated aqueous sodium carbonate. The organic layer wasdried over anhydrous sodium sulfate, filtered, and evaporated to afford7-(benzyloxy)-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolinein almost quantitative yield with some residual1,8-diazabicyclo[5.4.0]undec-7-ene as a brown oil, which was usedwithout further purification.

Part C

A mixture of7-(benzyloxy)-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline(4.6 g, 9.04 mmol) and palladium hydroxide (1.5 g) in acetonitrile (50mL) and methanol (75 mL) was hydrogenated on a Parr apparatus at 50 psi(3.5×10⁵ Pa) for 28 hours. The mixture was filtered through CELITEfilter agent, which was rinsed afterwards with 40% methanol inacetonitrile (600 mL). The filtrates were combined and concentratedunder reduced pressure to yield a yellow solid that was triturated withacetonitrile and isolated by filtration to afford 2.2 g of1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-olas a pale yellow powder.

Part D

Using a modification of the method described in Part A of Example 392,1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol(1.1 g, 2.63 mmol) was converted into1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline,using 3-hydroxytetrahydrofuran (0.320 mL, 3.94 mmol) in lieu of3-(methylthio)propan-1-ol. The reaction mixture was allowed to stir atambient temperature for 72 hours, then was treated with 3 M hydrochloricacid (30 mL) and extracted with ethyl acetate. The aqueous layer wasadjusted to a basic pH with saturated aqueous sodium carbonate and wasextracted with dichloromethane. The organic layer was washed with waterand saturated sodium chloride, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 1.0 g of1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolineas a yellow waxy solid.

Part E

Using a modification of the method described in Part B of Example 392,1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline(1.0 g, 2.05 mmol) was converted into1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine.In the workup, the layers were separated and the aqueous was extractedwith chloroform. The combined organic layers were washed with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,filtered, and evaporated under reduced pressure. The crude product wasrecrystallized from acetonitrile to 0.511 g of1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amineas red-tan crystals, mp 195.5-197° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (d, J=9.0 Hz, 1H), 7.02 (d, J=2.6 Hz,1H), 6.90 (dd, J=9.0, 2.6 Hz, 1H), 6.57 (s, 2H), 5.17-5.10 (m, 1H), 4.75(s, 2H), 4.58-4.48 (m, 2H), 3.97-3.74 (m, 4H), 3.55 (q, J=7.0 Hz, 2H),3.19-3.13 (m, 4H), 2.93 (t, J=6.6 Hz, 2H), 2.33-2.14 (m, 3H), 2.08-1.99(m, 1H), 1.92-1.82 (m, 2H), 1.76-1.66 (m, 2H), 1.16 (t, J=7.0 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 156.1, 152.3, 148.1, 146.9, 133.3, 124.9,121.7, 112.2, 109.0, 108.8, 77.0, 72.3, 66.5, 65.3, 64.2, 46.5, 46.1,45.0, 43.7, 32.5, 27.1, 24.3, 18.3, 14.9;

MS (ESI) m/z 504.2276 (504.2281 calcd for C₂₄H₃₃N₅O₅S, M+H⁺).

Anal. calcd for C₂₄H₃₃N₅O₅S: C, 57.24; H, 6.60; N, 13.91; S, 6.37.Found: C, 56.91; H, 6.47; N, 13.73; S, 6.50.

Example 4021-(3-{[4-Amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-one

Using a modification of the procedures described in Parts D and E ofExample 401,1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol(prepared as described in Steps A-C of Example 401, 1.1 g, 2.63 mmol)was converted into1-(3-{[4-amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-one,using 1-(3-hydroxypropyl)pyrrolidin-2-one in lieu of3-hydroxytetrahydrofuran in step D. Purification by chromatography on aHORIZON HPFC system (silica gel, gradient elution with 1-20% CMA inchloroform) followed by trituration with acetonitrile and isolation byfiltration afforded 0.551 g of1-(3-{[4-amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-oneas a white solid, mp 142-144° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (d, J=9.0 Hz, 1H), 7.05 (d, J=2.6 Hz,1H), 6.91 (dd, J=8.9, 2.6 Hz, 1H), 6.52 (s, 2H), 4.75 (s, 2H), 4.55-4.50(m, 2H), 4.04 (t, J=6.2 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.40-3.34 (m,4H), 3.18-3.13 (m, 4H), 2.94 (t, J=6.6 Hz, 2H), 2.24-2.14 (m, 4H),2.00-1.82 (m, 6H), 1.76-1.66 (m, 2H), 1.16 (t, J=7.0 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 173.9, 157.5, 152.3, 148.0, 147.0, 133.3,124.8, 121.4, 111.7, 108.7, 108.0, 65.3, 65.3, 64.1, 46.5, 46.1, 44.9,43.7, 39.1, 30.4, 27.1, 26.7, 24.3, 18.3, 17.5, 14.9;

MS (ESI) m/z 559.2718 (559.2703 calcd for C₂₇H₃₈N₆O₅S, M+H⁺).

Anal. calcd for C₂₇H₃₈N₆O₅S: C, 58.05; H, 6.86; N, 15.04. Found: C,57.95; H, 7.22; N, 15.15.

Example 4034-{2-[(4-Amino-1-isobutyl-2-methyl-1H-imidazo[4,5-c]quinolin-7-yl)oxy]ethyl}-N-cyclohexylpiperidine-1-carboxamide

The preparation of2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amineis described in Example 24. Cyclohexyl isocyanate (0.100 mL, 0.786 mmol)was added dropwise to a stirred solution of2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine(0.300 g, 0.786 mmol) in dichloromethane (10 mL) at 0° C. After 30minutes, the solution was concentrated under reduced pressure and theresulting residue was purified by flash chromatography (silica gel,sequential elution with 2% and 5% methanol in dichloromethane) followedby recrystallization from ethanol to afford 0.141 g of4-{2-[(4-amino-1-isobutyl-2-methyl-1H-imidazo[4,5-c]quinolin-7-yl)oxy]ethyl}-N-cyclohexylpiperidine-1-carboxamideas a white powder, mp 213.7-215.7° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (d, J=9.5 Hz, 1H), 7.05 (d, J=3.0 Hz,1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.43 (s, 2H), 6.06 (d, J=7.6 Hz, 1H),4.27 (d, J=7.5 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 4.0-3.92 (m, 2H),3.44-3.30 (m, 1H), 2.64-2.56 (m, 2H), 2.56 (s, 3H), 2.23-2.09 (m, 1H),1.77-1.50 (m, 10H), 1.3-0.96 (m, 7H), 0.93 (d, J=6.7 Hz, 6H);

MS (ESI) m/z 507.3465 (507.3448 calcd for C₂₉H₄₂N₆O₂, M+H⁺).

Anal. calcd for C₂₉H₄₂N₆O₂.0.5H₂O: C, 67.54; H, 8.41; N, 16.30. Found:C, 67.78; H, 8.43; N, 16.46.

Example 404 tert-Butyl4-({[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}acetyl)piperazine-1-carboxylate

Part A

Di-tert-butyl dicarbonate (19.05 g, 0.087 mol) in dichloromethane (218mL) was added dropwise over 2 hours to a solution of piperazine (15.0 g,0.174 mol) in dichloromethane (436 mL). The reaction mixture was allowedto stir for 16 hours, then the solution was concentrated under reducedpressure to yield a solid that was treated with water (500 mL). Themixture was stirred vigorously and a white solid was isolated byfiltration and washed with water. The solid was discarded. The filtratewas extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to yield 12.7 g of tert-butyl piperazine-1-carboxylate as clearyellow crystals.

Part B

Bromoacetyl bromide (2.97 mL, 34.1 mmol) in dichloromethane (25 mL) wasadded dropwise to the solution of tert-butyl piperazine-1-carboxylate(6.35 g, 34.1 mmol) and diisopropylethylamine (5.8 mL, 33.3 mmol) indichloromethane (38 mL) at 0° C. The solution was allowed to warm toambient temperature and was stirred for 2 hours, then was poured into aseparatory funnel. The solution was washed with water, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. Purification by flash chromatography (silica gel, elutingsequentially with 20%, 33%, and finally 50% ethyl acetate in hexanes)afforded 4.05 g of tert-butyl 4-(2-bromoacetyl)piperazine-1-carbamate asa brown crystalline solid.

Part C

The synthesis of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described inParts A-I of Example 2. A mixture of2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (4.5 g, 15.8mmol), tert-butyl 4-(2-bromoacetyl)piperazine-1-carbamate (4.57 g, 14.9mmol), and potassium carbonate (3.27 g, 23.7 mmol) in DMF (158 mL) washeated to 55° C. for 2.5 hours, then was allowed to cool to roomtemperature and was stirred for 16 hours. The solution was poured intowater (500 mL), which was extracted with diethyl ether (300 mL), ethylacetate (300 mL) and dichloromethane (300 mL). The combined organiclayers were concentrated under reduced pressure. The crude product waspurified by flash chromatography (silica gel, gradient elution with 0-5%methanol in dichloromethane to provide 7.9 g of tert-butyl4-({[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}acetyl)piperazine-1-carboxylateas a tan waxy solid that contained 15% of DMF by weight.

Part D

The material from Part C was dissolved in chloroform (150 mL) andtreated with mCPBA (70% w/w, 3.80 g, 15.4 mmol). The solution wasstirred for 30 minutes, and additional mCPBA (1.0 g) was added. After 1hour, the reaction was diluted with chloroform (150 mL) and washed with1:1 saturated aqueous sodium carbonate/water. The layers were separatedand the aqueous layer was extracted with chloroform. The organic layerswere combined, washed with water and saturated aqueous sodium chloride,dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford 14.9 g of approximately 54% pure tert-butyl4-({[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}acetyl)piperazine-1-carboxylatewas isolated as a red-orange oil, which was used in the next stepwithout purification.

Part E

A modification of the procedure described in Part C of Example 393 wasused to convert the material from Part D into tert-butyl4-({[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}acetyl)piperazine-1-carboxylate.After the p-toluenesulfonyl chloride (2.93 g, 15.4 mmol) was added, thereaction mixture was allowed to stir for 1 hour, then the ice bath wasreplaced with a water bath and the reaction mixture was allowed to stirfor 16 hours. The mixture was diluted with dichloromethane and thelayers were separated. The reaction was worked up as described inExample 393 and the crude product was recrystallized from acetonitrileto yield 4.7 g of tert-butyl4-({[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}acetyl)piperazine-1-carboxylateas tan crystals, mp 192-197° C. (decomposition).

¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=9.1 Hz, 1H), 7.41 (d, J=2.7 Hz,1H), 7.15 (dd, J=9.1, 2.6 Hz, 1H), 6.36 (s, 2H), 4.96 (s, 2H), 4.77 (s,2H), 4.54-4.49 (m, 2H), 3.59-3.31 (m, 10H), 1.93-1.81 (m, 2H), 1.41 (s,9H), 1.16 (t, J=7.0 Hz, 3H), 1.02 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 166.4, 153.7, 152.5, 150.6, 149.0, 140.2,132.7, 127.5, 126.6, 117.0, 114.4, 102.8, 79.2, 66.9, 65.3, 64.2, 46.7,44.2, 41.1, 28.0, 23.3, 14.9, 10.8;

MS (ESI) m/z 527.2992 (527.2982 calcd for C₂₇H₃₈N₆O₅, M+H⁺).

Anal. calcd for C₂₇H₃₈N₆O₅: C, 61.58; H, 7.27; N, 15.96. Found: C,61.41; H, 7.49; N, 15.96.

Example 4051-(3-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one

Part A

The synthesis of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described inParts A-I of Example 2. A modification of the method described in Part Aof Example 392 was used to convert2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (1.5 g, 5.26mmol) into1-[3-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)propyl]-pyrrolidin-2-oneusing 1-(3-hydroxypropyl)pyrrolidin-2-one (1.02 mL, 7.88 mL) in lieu of3-(methylthio)propan-1-ol. After the reaction mixture was allowed tostir for 16 hours at ambient temperature, additional diisopropylazodicarboxylate, triphenylphosphine, and1-(3-hydroxypropyl)pyrrolidin-2-one (0.5 equivalent of each) were addedand the reaction mixture was allowed to stir for 2 hours. The solventwas removed under reduced pressure and the resulting residue waspurified by flash chromatography (silica gel, elution with ethyl acetatefollowed by gradient elution with 1-5% methanol in dichloromethane) toyield 2.9 g of1-[3-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)propyl]-pyrrolidin-2-onea pale yellow solid.

Part B

3-Chloroperoxybenzoic acid (50% pure, 1.8 g, 5.26 mmol) was added to asolution of1-[3-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)propyl]-pyrrolidin-2-one(2.9 g, 5.26 mmol) in chloroform (50 mL). After 30 minutes, saturatedaqueous sodium carbonate (20 mL) was added to the solution and theresulting mixture was allowed to stir for 1 hour. The layers wereseparated and the aqueous layer was extracted with chloroform (3×50 mL).The organic layers were combined, washed with water and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The crude product was purifiedby flash chromatography (silica gel, gradient elution with 1-4% methanolin dichloromethane) to yield 1.56 g of1-(3-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-oneas a tan foam.

Step C

p-Toluenesulfonyl chloride (0.700 g, 3.66 mmol) was added to a stirredmixture of1-(3-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one(1.56 g, 3.66 mmol), ammonium hydroxide (24 mL), and dichloromethane (36mL) at room temperature. After 16 hours, the layers were separated andthe aqueous layer was extracted with dichloromethane (3×50 mL). Theorganic layers were combined, washed with water and saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. Recrystallization from acetonitrileafforded 0.759 g of1-(3-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-oneas off-white needles, mp 188.5-190° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.54 (d, J=9.1 Hz, 1H), 7.36 (d, J=2.6 Hz,1H), 7.11 (dd, J=9.1, 2.6 Hz, 1H), 6.33 (s, 2H), 4.76 (s, 2H), 4.53-4.48(m, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.54 (q, J=7.0 Hz, 2H), 3.37 (t, J=7.0Hz, 4H), 2.22-2.17 (m, 2H), 2.00-1.83 (m, 6H), 1.15 (t, J=7.0 Hz, 3H),1.02 (t, J=7.3 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 173.8, 153.0, 150.5, 148.9, 140.0, 132.7,127.6, 126.6, 117.2, 114.6, 102.3, 65.8, 65.3, 64.2, 46.8, 46.4, 39.1,30.4, 26.8, 23.3, 17.5, 14.9, 10.7;

MS (ESI) m/z 426.2518 (426.2505 calcd for C₂₃H₃₁N₅O₃, M+H⁺.

Anal. calcd for C₂₃H₃₁N₅O₃: C, 64.92; H, 7.34; N, 16.46. Found: C,64.80; H, 6.99; N, 16.37.

Example 4062-(Ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine

The synthesis of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described inParts A-I of Example 2. A modification of the method described in Part Aof Example 405 was used to convert2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol into2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolineusing 3-hydroxytetrahydrofuran in lieu of1-(3-hydroxypropyl)pyrrolidin-2-one. Modifications of the methodsdescribed in Parts B and C of Example 405 were used to convert2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolineinto2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine.Parts B and C were combined by omitting the aqueous work up of Part B,in other words, the ammonium hydroxide and p-toluenesulfonyl chloridereagents used in Part C were added to the reaction mixture in Part B.The reaction was worked up as described in Part C of Example 405.2-(Ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-aminewas isolated as tan needles, mp 173-175° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=9.1 Hz, 1H), 7.34 (d, J=2.7 Hz,1H), 7.11 (dd, J=9.1, 2.6 Hz, 1H), 6.36 (s, 2H), 5.21-5.14 (m, 1H), 4.78(s, 2H), 4.58-4.48 (m, 2H), 3.97-3.76 (m, 4H), 3.56 (q, J=7.0 Hz, 2H),2.31-2.19 (m, 1H), 2.13-2.04 (m, 1H), 1.97-1.84 (m, 2H), 1.16 (t, J=7.0Hz, 3H), 1.02 (t, J=7.4 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 151.5, 150.6, 148.9, 140.4, 132.6, 127.8,126.7, 117.8, 114.6, 103.3, 77.4, 72.2, 66.4, 65.3, 64.2, 46.8, 32.3,23.3, 14.9, 10.8;

MS (ESI) m/z 371.2084 (371.2083 calcd for C₂₀H₂₆N₄O₃, M-+H⁺).

Anal. calcd for C₂₀H₂₆N₄O₃: C, 64.85; H, 7.07; N, 15.12. Found: C,64.50; H, 7.09; N, 15.29.

Example 407N-(6-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-2-methylpropanamide

Part A

The synthesis of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described inParts A-I of Example 2. The general method described in Part L ofExample 2 was followed.2-(Ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (4.43 g, 15.5mmol) was treated with tert-butyl 6-iodohexylcarbamate (prepared asdescribed in Part F of Example 45, 6.1 g, 18.6 mmol). After the work up,the crude product was not purified to yield 9.9 g of tert-butyl6-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexylcarbamateas a tan waxy solid that contained DMF and dichloromethane.

Part B

A modification of the procedure described in Part B of Example 392 wasused to convert the crude tert-butyl6-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexylcarbamatefrom Part A into tert-butyl6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexylcarbamate.The reaction mixture was transferred to a separatory funnel and thelayers were separated. The aqueous layer was extracted withdichloromethane (2×100 mL). The organic layers were combined, washedwith 5% aqueous sodium bicarbonate, water, and saturated aqueous sodiumchloride. The organic layer was then dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel, gradientelution 1-5% methanol in dichloromethane) to afford 4.60 g of tert-butyl6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexylcarbamateas a tan solid that contained some impurities but was used in the nextstep without further purification.

Part C

A solution of the material from Part B in 4.0 M ethanolic hydrogenchloride (22 mL) was heated at reflux for 1 hour. The solution wasallowed to cool to room temperature and was concentrated under reducedpressure to yield an oily residue. Water (approximately 10 mL) andsaturated aqueous sodium chloride (10 mL) were added to the oilyresidue, then the solution was adjusted to approximately pH 13 with 50%aqueous sodium hydroxide. The aqueous solution was extracted with 9:1chloroform/methanol (2×100 mL). The organic layers were combined, driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The crude product was triturated with acetonitrile anda solid was isolated by filtration to afford 3.1 g of8-(6-aminohexyloxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamineas a pale violet solid.

Part D

Isobutyryl chloride (0.236 mL, 2.25 mmol) was added dropwise, followedby triethylamine (0.2 mL, 1.4 mmol), to a stirred slurry of8-(6-aminohexyloxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(0.900 g, 2.25 mmol) in dichloromethane (25 mL) at room temperature.After 30 minutes, water (15 mL) was added and the mixture was allowed tostir for 30 minutes. The layers were separated and the aqueous layer wasextracted with dichlormethane. The organic layers were combined, washedwith water and brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. Purification by flashchromatography (silica gel, gradient elution with 1-6% CMA inchloroform) followed by recrystallization from acetonitrile afforded0.285 g ofN-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-2-methylpropanamideas a white crystalline solid, mp 136-138° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.64 (t, J=5.5 Hz, 1H), 7.53 (d, J=9.1 Hz,1H), 7.35 (d, J=2.6 Hz, 1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.31 (s, 2H),4.76 (s, 2H), 4.53-4.48 (m, 2H), 4.07 (t, J=6.5 Hz, 2H), 3.54 (q, J=7.0Hz, 2H), 3.02 (q, J=6.1 Hz, 2H), 2.37-2.23 (m, 1H), 1.96-1.83 (m, 2H),1.80-1.71 (m, 2H), 1.50-1.26 (m, 6H), 1.15 (t, J=7.0 Hz, 3H), 1.02 (t,J=7.4 Hz, 3H), 0.96 (d, J=6.9 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 175.8, 153.2, 150.5, 148.8, 139.9, 132.7,127.6, 126.6, 117.2, 114.6, 102.1, 67.6, 65.3, 64.2, 46.7, 38.2, 34.0,29.1, 28.7, 26.1, 25.3, 23.3, 19.6, 14.9, 10.7;

MS (ESI) m/z 470.3118 (470.3131 calcd for C₂₆H₃₉N₅O₃, M+H⁺).

Anal. calcd for C₂₆H₃₉N₅O₃: C, 66.50; H, 8.37; N, 14.91. Found: C,66.24; H, 8.35; N, 14.77.

Example 408N-(6-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-N′-isopropylurea

A modification of the procedure described in Part A of Example 369 wasused to convert8-(6-aminohexyloxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(prepared as described in Parts A-C of Example 407, 0.900 g, 2.25 mmol)intoN-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-N′-isopropylurea.The crude product was purified by flash chromatography followed byrecrystallization from acetonitrile to provide 0.528 g ofN-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-N′-isopropylureaas flocculent white crystals, mp 167-169° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.53 (d, J=9.1 Hz, 1H), 7.35 (d, J=2.6 Hz,1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.31 (s, 2H), 5.63 (t, J=5.6 Hz, 1H),5.54 (d, J=7.7 Hz, 1H), 4.76 (s, 2H), 4.53-4.48 (m, 2H), 4.07 (t, J=6.5Hz, 2H), 3.70-3.57 (m, 1H), 3.54 (q, J=7.0 Hz, 2H), 2.96 (q, J=6.1 Hz,2H), 1.96-1.83 (m, 2H), 1.80-1.71 (m, 2H), 1.49-1.26 (m, 6H), 1.15 (t,J=7.0 Hz, 3H), 1.02 (t, J=7.3 Hz, 3H), 0.98 (d, J=6.5 Hz, 6H);

¹³C NMR (75 MHz, DMSO-d₆) δ 157.4, 153.2, 150.5, 148.8, 139.9, 132.7,127.6, 126.6, 117.2, 114.6, 102.1, 67.7, 65.3, 64.2, 46.8, 40.7, 39.0,30.0, 28.7, 26.2, 25.3, 23.3, 23.2, 14.9, 10.7;

MS (ESI) m/z 485.3237 (485.3240 calcd for C₂₆H₄₀N₆O₃, M+H⁺).

Anal. calcd for C₂₆H₄₀N₆O₃: C, 64.44; H, 8.32; N, 17.34. Found: C,64.15; H, 8.43; N, 17.21.

Example 409N-(6-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)methanesulfonamide

A modification of the procedure described in Part D of Example 407 wasused to convert8-(6-aminohexyloxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine(prepared as described in Parts A-C of Example 407, 0.900 g, 2.25 mmol)intoN-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)methanesulfonamide.The reaction was run using methanesulfonyl chloride (0.174 mL, 2.25mmol) in lieu of isobutyryl chloride and without triethylamine. Thereaction was quenched with saturated aqueous sodium carbonate (10 mL)instead of water. The crude product was purified by flash chromatographyfollowed by recrystallization from acetonitrile to afford 0.350 g ofN-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)methanesulfonamideas flocculent white crystals, mp 164-167° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.53 (d, J=9.1 Hz, 1H), 7.36 (d, J=2.6 Hz,1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.91 (t, J=5.8 Hz, 1H), 6.31 (s, 2H),4.76 (s, 2H), 4.54-4.48 (m, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.54 (q, J=7.0Hz, 2H), 2.92 (q, J=6.6 Hz, 2H), 2.86 (s, 3H), 1.96-1.84 (m, 2H),1.81-1.72 (m, 2H), 1.53-1.31 (m, 6H), 1.15 (t, J=7.0 Hz, 3H), 1.02 (t,J=7.4 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 153.2, 150.5, 148.8, 139.9, 132.7, 127.6,126.6, 117.2, 114.6, 102.1, 67.6, 65.3, 64.2, 46.8, 42.4, 39.1, 29.4,28.6, 25.9, 25.2, 23.3, 14.9, 10.7;

MS (ESI) m/z 478.2485 (478.2488 calcd for C₂₃H₃₅N₅O₄S, M+H⁺).

Anal. calcd for C₂₃H₃₅N₅O₄S: C, 57.84; H, 7.39; N, 14.66. Found: C,57.97; H, 7.60; N, 14.67.

Example 410 tert-Butyl4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate

Part A

The synthesis of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described inParts A-I of Example 2. The general method described in Part A ofExample 374 was followed starting with2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (6.0 g, 21.0mmol). The crude product was purified by flash chromatography (silicagel, gradient elution with 1-7% CMA in chloroform) to yield 9.76 g oftert-butyl4-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylateas a slightly impure tan semi-solid that was used in the next stepwithout further purification.

Part B

A solution of the material from Part A (9.7 g, 20.7 mmol) and 32%peracetic acid in acetic acid (7.36 mL, 31.0 mmol) in ethyl acetate (69mL) was heated at 50° C. for 3.5 hours. A solution of sodiummetabisulfite (4.92 g, 25.9 mmol) in water (10 mL) was added over 15minutes. The reaction mixture was allowed to stir at 50° C. for 30minutes. Heating was discontinued and the reaction was adjusted to pH 10with 50% aqueous sodium hydroxide. The mixture was allowed to cool toambient temperature and was transferred to a separatory funnel. Thelayers were separated and the aqueous layer was extracted with ethylacetate. The organic layers were combined and washed with water andsaturated aqueous sodium chloride. The aqueous layers were combined andwere back-extracted with dichloromethane. All the organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 10-22% CMA in chloroform) to yield 4.5 g of tert-butyl4-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylateas a orange-white solid.

Part C

Trichloroacetyl isocyanate (1.22 mL, 10.2 mmol) was added dropwise astirred solution of tert-butyl4-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate(4.5 g, 9.29 mmol) in dichloromethane (90 mL) at room temperature. After1.5 hours, ammonium hydroxide (4.5 mL) was added and the mixture wasallowed to stir for 1 hour. Saturated aqueous sodium carbonate (60 mL)and water (20 mL) were added to the mixture. After 30 minutes, themixture was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was extracted with chloroform (2×100 mL).The organic layers were combined, washed with water and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The crude product was purifiedby chromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 1-25% CMA in chloroform) followed by recrystallization fromacetonitrile to yield 2.3 g of tert-butyl4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylateas a gray solid, mp 179.5-181° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=9.0 Hz, 1H), 7.42 (d, J=2.5 Hz,1H), 7.16 (dd, J=9.0, 2.6 Hz, 1H), 6.36 (s, 2H), 4.77 (s, 2H), 4.69-4.61(m, 1H), 4.55-4.50 (m, 2H), 3.75-3.65 (m, 2H), 3.56 (q, J=7.0 Hz, 2H),3.28-3.15 (m, 2H), 2.01-1.82 (m, 4H), 1.68-1.54 (m, 2H), 1.41 (s, 9H),1.16 (t, J=7.0 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 484.5 (M+H)⁺;

Anal. calcd for C₂₆H₃₇N₅O₄: C, 64.57; H, 7.71; N, 14.48. Found: C,64.33; H, 7.91; N, 14.52.

Example 4112-(Ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

A solution of tert-butyl4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate(prepared as described in Example 410, 2.9 g, 6.0 mmol) and 4 Methanolic hydrogen chloride (15 mL) in ethanol (20 mL) was heated atreflux for 2 hours. The solution was allowed to cool to ambienttemperature and was concentrated under reduced pressure to approximately17 mL, causing a solid to form. Water was added to dissolve the solidand the remainder of the ethanol was evaporated under reduced pressure.The aqueous solution was adjusted to approximately pH 13 with 50%aqueous sodium hydroxide, then was extracted with chloroform. Theorganic layers were combined, washed with water and saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The product was recrystallizationfrom acetonitrile to yield 1.25 g of2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas off-white needles, mp 176-178° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.54 (d, J=9.0 Hz, 1H), 7.39 (d, J=2.6 Hz,1H), 7.11 (dd, J=9.0, 2.6 Hz, 1H), 6.33 (s, 2H), 4.77 (s, 2H), 4.54-4.44(m, 3H), 3.56 (q, J=7.0 Hz, 2H), 3.02-2.95 (m, 2H), 2.62-2.54 (m, 2H),2.07-1.83 (m, 5H), 1.57-1.45 (m, 2H), 1.16 (t, J=7.0 Hz, 3H), 1.04 (t,J=7.4 Hz, 3H);

¹³C NMR (75 MHz, DMSO-d₆) δ 151.4, 150.5, 148.8, 140.0, 132.6, 127.7,126.6, 118.5, 114.6, 104.0, 74.1, 65.3, 64.2, 46.8, 43.8, 32.4, 23.3,14.9, 10.7;

MS (ESI) m/z 384.2414 (384.2400 calcd for C₂₁H₂₉N₅O₂, M+H⁺).

Anal. calcd for C₂₁H₂₉N₅O₂: C, 65.77; H, 7.62; N, 18.26. Found: C,65.55; H, 7.60; N, 18.17.

Example 4124-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}-N-isopropylpiperidine-1-carboxamide

Isopropyl isocyanate (0.190 mL, 1.90 mmol) was added dropwise to asolution of2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(prepared as described in Example 411, 0.730 g, 1.90 mmol) indichloromethane (15 mL) at room temperature. The reaction was dilutedwith dichloromethane and stirred vigorously. A precipitate formed thatwas isolated by filtration to afford 0.743 g of4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}-N-isopropylpiperidine-1-carboxamideas a white solid, mp 236.5-239° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=9.0 Hz, 1H), 7.42 (d, J=2.5 Hz,1H), 7.15 (dd, J=9.0, 2.5 Hz, 1H), 6.35 (s, 2H), 6.20 (t, J=7.6 Hz, 1H),4.78 (s, 2H), 4.67-4.59 (m, 1H), 4.55-4.50 (m, 2H), 3.82-3.69 (m, 3H),3.56 (q, J=7.0 Hz, 2H), 3.16-3.07 (m, 2H), 2.01-1.82 (m, 4H), 1.65-1.49(m, 2H), 1.16 (t, J=7.0 Hz, 3H), 1.06 (d, J=6.6 Hz, 6H), 1.03 (t, J=7.4Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 156.7, 151.3, 150.6, 148.9, 140.2, 132.6,127.7, 126.6, 118.4, 114.7, 104.6, 73.0, 65.3, 64.2, 46.7, 41.7, 40.9,30.5, 23.2, 22.9, 14.9, 10.8;

MS (ESI) m/z 469.2936 (469.2927 calcd for C₂₅H₃₆N₆O₃, M+H⁺).

Anal. calcd for C₂₅H₃₆N₆O₃: C, 64.08; H, 7.74; N, 17.93. Found: C,63.85; H, 7.67; N, 17.89.

Example 4132-(Ethoxymethyl)-8-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Methanesulfonic anhydride (0.295 g, 1.69 mmol) was added in one portionto a stirred solution of2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(prepared as described in Example 411, 0.650 g, 1.69 mmol) indichloromethane (15 mL) at room temperature, resulting in a whiteprecipitate. After 16 hours, 2.0 M aqueous sodium carbonate was addedand the reaction mixture was allowed to stir for 45 minutes. Theprecipitate dissolved and the mixture was transferred to a separatoryfunnel where the layers were separated. The aqueous layer was extractedwith chloroform. The organic layers were combined, washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The crude product was purified by trituration inboiling acetonitrile and isolated by filtration to yield 0.650 g of2-(ethoxymethyl)-8-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white crystalline solid, mp 240-243.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.57 (d, J=9.0 Hz, 1H), 7.43 (d, J=2.5 Hz,1H), 7.18 (dd, J=9.0, 2.5 Hz, 1H), 6.38 (s, 2H), 4.78 (s, 2H), 4.70-4.61(m, 1H), 4.55-4.50 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.44-3.36 (m, 2H),3.20-3.12 (m, 2H), 2.92 (s, 3H), 2.10-2.00 (m, 2H), 1.95-1.79 (m, 4H),1.16 (t, J=7.0 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 151.3, 150.7, 148.9, 140.3, 132.6, 127.7,126.6, 118.4, 114.7, 105.0, 71.4, 65.3, 64.2, 46.7, 42.5, 34.4, 29.8,23.2, 14.9, 10.8;

MS (ESI) m/z 462.2172 (462.2175 calcd for C₂₂H₃₁N₅O₄S, M+H⁺).

Anal. calcd for C₂₂H₃₁N₅O₄S.0.15CHCl₃: C, 55.49; H, 6.55; N, 14.61; Cl,3.33. Found: C, 55.51; H, 6.71; N, 14.66; Cl, 3.25.

Example 4142-(Ethoxymethyl)-8-[(1-isobutyrylpiperidin-4-yl)oxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

A modification of the procedure described in Example 413 was used.2-(Ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(prepared as described in Example 411, 0.650 g, 1.69 mmol) was treatedwith isobutyryl chloride instead of the methanesulfonic anhydride. Afterthe work up, the crude product was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution with 2-25% CMA inchloroform) followed by recrystallization from acetonitrile to yield0.500 g of2-(ethoxymethyl)-8-[(1-isobutyrylpiperidin-4-yl)oxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, mp 177-179° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=9.0 Hz, 1H), 7.44 (d, J=2.6 Hz,1H), 7.17 (dd, J=9.1, 2.6 Hz, 1H), 6.36 (s, 2H), 4.78 (s, 2H), 4.78-4.68(m, 1H), 4.55-4.50 (m, 2H), 3.96-3.74 (m, 2H), 3.56 (q, J=7.0 Hz, 2H),3.46-3.36 (m, 1H), 2.98-2.83 (m, 1H), 2.09-1.80 (m, 4H), 1.76-1.53 (m,2H), 1.16 (t, J=7.0 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H), 1.01 (d, J=6.7 Hz,6H);

¹³C NMR (125 MHz, DMSO-d₆) δ 174.1, 151.2, 150.6, 148.9, 140.2, 132.6,127.7, 126.6, 118.3, 114.6, 104.8, 72.6, 65.3, 64.2, 46.7, 41.9, 38.3,31.3, 30.3, 28.9, 23.2, 19.4, 14.9, 10.7;

MS (ESI) m/z 454.2819 (454.2818 calcd for C₂₅H₃₅N₅O₃, M+H⁺).

Anal. calcd for C₂₅H₃₅N₅O₃: C, 66.20; H, 7.78; N, 15.44. Found: C,66.05; H, 7.72; N, 15.57.

Example 415 tert-Butyl4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate

Part A

2-(Ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (3.00 g, 10.5mmol) and triphenylphosphine (3.43 g, 13.1 mmol) were slurried in THF(105 mL) and cooled with an ice/water bath. tert-Butyl4-hydroxypiperidine-1-carboxylate (2.64 g, 13.1 mmol) was added followedby the dropwise addition of diisopropyl azodicarboxylate (2.58 mL, 13.1mmol). The water bath was removed and the mixture was stirred for 72hours under nitrogen. The solvent was removed under reduced pressure andthe residue was purified by chromatography on a HORIZON HPFC system(silica gel, gradient elution with 1-15% CMA in chloroform) to afford5.17 g of tert-butyl4-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas an off-white crystalline solid.

Part B

To a stirring solution of tert-butyl4-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(5.17 g, 10.5 mmol) in chloroform (100 mL) was added3-chloroperoxybenzoic acid (3.62 g, 10.5 mmol, based on 50% purity).After 30 minutes, concentrated ammonium hydroxide (50 mL) was added andthe mixture was stirred for 30 minutes. p-Toluenesulfonyl chloride (2.00g, 10.5 mmol) was added in 3 portions and the mixture was stirred for 16hours. The layers were separated and the organic fraction wassequentially washed with 5% aqueous sodium bicarbonate, water, andsaturated aqueous sodium chloride. The organic fraction was dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. Recrystallization from acetonitrile afforded 2.58 g oftert-butyl4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas a reddish-tan crystalline solid, mp 194-195° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=9.0 Hz, 1H), 7.11 (d, J=2.6 Hz,1H), 6.95 (dd, J=9.0, 2.6 Hz, 1H), 6.51 (s, 2H), 4.75 (s, 2H), 4.71-4.60(m, 1H), 4.53-4.41 (m, 2H), 3.77-3.65 (m, 2H), 3.56 (q, J=7.0 Hz, 2H),3.27-3.12 (m, 2H), 2.03-1.91 (m, 2H), 1.91-1.78 (m, 2H), 1.64-1.49 (m,2H), 1.41 (s, 9H), 1.16 (t, J=7.0 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 484.3 (M+H)⁺;

Anal. calcd for C₂₆H₃₇N₅O₄: C, 64.57; H, 7.71; N, 14.48. Found: C,64.36; H, 7.66; N, 14.65.

Example 4162-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

tert-Butyl4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(2.45 g, 5.07 mmol) was taken up in 4.0M ethanolic hydrogen chloride (15mL) and heated to 65° C. for 1 hour. The heat was removed and thereaction was allowed to cool to ambient temperature. The ethanol wasremoved under reduced pressure and the solid residue was dissolved inwater (10 mL) and saturated aqueous sodium chloride (10 mL). Thesolution was brought to pH 13 with 50% aqueous sodium hydroxide and thenextracted with chloroform. The organic fraction was sequentially washedwith water and saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and evaporated. Trituration with acetonitrile,followed by filtration afforded 1.70 g of2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a tan solid, mp 202-204° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=9.0 Hz, 1H), 7.07 (d, J=2.5 Hz,1H), 6.92 (dd, J=9.0, 2.5 Hz, 1H), 6.51 (s, 2H), 4.74 (s, 2H), 4.54-4.39(m, 3H), 3.55 (q, J=7.0 Hz, 2H), 3.03-2.90 (m, 2H), 2.67-2.54 (m, 2H),2.03-1.78 (m, 5H), 1.57-1.40 (m, 2H), 1.16 (t, J=7.0 Hz, 3H), 1.00 (t,J=7.3 Hz, 3H);

MS (ESI) m/z 384.2 (M+H)⁺;

Anal. calcd for C₂₁H₂₉N₅O₂: C, 65.77; H, 7.62; N, 18.26. Found: C,65.61; H, 7.62; N, 18.23.

Example 4174-{[4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamide

2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Isopropylisocyanate was added dropwise to the slurry and the reaction was stirredfor 16 hours. The reaction was purified by chromatography on a HORIZONHPFC system (silica gel, gradient elution with 2-22% CMA in chloroform)followed by recrystallization from acetonitrile yielded 0.430 g of4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamideas a white solid, mp 163-164.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=9.0 Hz, 1H), 7.11 (d, J=2.6 Hz,1H), 6.94 (dd, J=9.0, 2.6 Hz, 1H), 6.52 (s, 2H), 6.19 (d, J=7.6 Hz, 1H),4.75 (s, 2H), 4.58-4.52 (m, 1H), 4.52-4.41 (m, 2H), 3.84-3.66 (m, 3H),3.55 (q, J=7.0 Hz, 2H), 3.18-3.04 (m, 2H), 2.02-1.77 (m, 4H), 1.62-1.44(m, 2H), 1.16 (t, J=7.0 Hz, 3H), 1.06 (d, J=6.6 Hz, 6H), 1.00 (t, J=7.3Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 156.7, 155.9, 152.3, 148.1, 147.0, 133.4,124.9, 121.4, 112.6, 109.8, 108.9, 72.3, 65.3, 64.2, 46.7, 41.7, 40.9,30.5, 23.0, 22.9, 14.9, 10.7;

MS (APCI) m/z 469.3 (M+H)⁺;

Anal. calcd for C₂₅H₃₆N₆O₃.0.4H₂O: C, 63.11; H, 7.80; N, 17.66. Found:C, 63.20; H, 7.94; N, 17.92.

Examples 418-422

A solution of 1 M boron tribromide in heptane (400 μL) was added to a 0°C., stirred solution of a starting material from the table below(approximately 25 mg) in dichloromethane (1 mL). The reaction mixturewas stirred at 0° C. for 30 minutes and then at room temperatureovernight. Methanol (1 mL) and 6 M aqueous hydrochloric acid (250 μL)was added to each reaction vessel, which was vortexed shortlyafterwards. The volatiles were removed by vacuum centrifugation. Thecompounds were purified using the method described in Examples 376-386.The table below shows the starting material added to each reactionvessel, the structure of the resulting compound, and the observedaccurate mass for the isolated trifluoroacetate salt.

Examples 418-422

Measured Starting Mass Example Material R (M + H) 418 Example 56

357.1910 419 Example 366

372.2025 420 Example 394

344.2099 421 Example 389

440.2666 422 Example 388

455.2815

Examples 423-438

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing3-[4-amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride (45 mg, 0.1 mmol, prepared as described in Example 373)and N,N-diisopropylethylamine (0.071 mL, 0.40 mmol) inN,N-dimethylacetamide (1 mL). The test tubes were capped and shakenovernight at room temperature and then two drops of water were added toeach test tube. The solvent was removed by vacuum centrifugation. Thecompounds were purified using the method described in Examples 376-386.The table below shows the reagent added to each test tube, the structureof the resulting compound, and the observed accurate mass for theisolated trifluoroacetate salt.

Examples 423-438

Measured Mass Example Reagent R (M + H) 423 None

376.2022 424 Acetyl chloride

418.2082 425 Cyclopropanecarbonyl chloride

444.2210 426 Butyryl chloride

446.2388 427 Isobutyryl chloride

446.2406 428 Benzoyl chloride

480.2225 429 Isonicotinoyl chloride hydrochloride

481.2214 430 Nicotinoyl chloride hydrochloride

481.2206 431 Methanesulfonyl chloride

454.1791 432 Ethanesulfonyl chloride

468.1954 433 1-Propanesulfonyl chloride

482.2046 434 Isopropylsulfonyl chloride

482.2057 435 Dimethylsulfamoyl chloride

483.2048 436 1-Butanesulfonyl chloride

496.2247 437 Benzenesulfonyl chloride

516.1933 438 1-Methylimidazole-4- sulfonyl chloride

520.1968

Examples 439-459

The free base of3-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride (prepared as described in Example 375) was prepared. Areagent (0.11 mmol, 1.1 equivalents) from the table below was added to atest tube containing3-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol(42 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.20 mmol)in N,N-dimethylacetamide (1 mL). The test tubes were capped and shakenovernight at room temperature and then two drops of water were added toeach test tube. The solvent was removed by vacuum centrifugation. Thecompounds were purified using the method described in Examples 376-386.The table below shows the reagent added to each test tube, the structureof the resulting compound, and the observed accurate mass for theisolated trifluoroacetate salt.

Examples 439-459

Measured Ex- Mass ample Reagent R (M + H) 439 None

416.2302 440 Methyl chloroformate

474.2354 441 Cyclopropane- carbonyl chloride

484.2601 442 Isobutyryl chloride

486.2735 443 Cyclopentane- carbonyl chloride

512.2896 444 Cyclohexane- carbonyl chloride

526.3023 445 Isonicotinoyl chloride hydrochloride

521.2510 446 Nicotinoyl chloride hydrochloride

521.2501 447 Benzenesulfonyl chloride

556.2224 448 1-Methylimidazole- 4-sulfonyl chloride

560.2277 449 Methyl isocyanate

473.2537 450 Ethyl isocyanate

487.2658 451 Isopropyl isocyanate

501.2823 452 Cyclopentyl isocyanate

527.2974 453 Phenyl isocyanate

535.2666 454 N,N- Dimethylcarbamoyl chloride

487.2687 455 1-Pyrrolidine- carbonyl chloride

513.2853 456 1-Piperidinecarbonyl chloride

527.3002 457 4- Morpholinecarbonyl chloride

529.2791 458 4-Methyl-1- piperazinecarbonyl chloride

542.3113 459 N-Methyl-N- phenylcarbamoyl chloride

549.2811

Examples 460-477

The free base of3-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-dioldihydrochloride (prepared as described in Example 375) was prepared. Analdehyde or ketone (0.125 mmol, 1.25 equivalents) from the table belowwas added to a test tube containing3-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol(42 mg, 0.10 mmol) in N,N-dimethylacetamide (1 mL). The test tubes werecapped and shaken for 30 minutes at room temperature. Borane-pyridinecomplex (16 μL, 0.13 mmol) was added to each of the tubes. The testtubes were capped and shaken overnight at room temperature, then twodrops of water were added to each test tube. The solvent was removed byvacuum centrifugation. The compounds were purified using the methoddescribed in Examples 376-386. The table below shows the aldehyde orketone added to each test tube, the structure of the resulting compound,and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 460-477

Measured Ex- Mass ample Reagent R (M + H) 460 None

416.2328 461 Cyclopropane- carboxaldehyde

470.2766 462 Isobutyraldehyde

472.2943 463 Butyraldehyde

472.2970 464 Tetrahydrofuran-3- carboxaldehyde

500.2865 465 Benzaldehyde

506.2785 466 Picolinaldehyde

507.2712 467 1-Methyl-2- imidazole- carboxaldehyde

510.2865 468 m-Tolualdehyde

520.2944 469 o-Tolualdehyde

520.2950 470 p-Tolualdehyde

520.2921 471 Phenylacetaldehyde

520.2942 472 2-Fluorobenzaldehyde

524.2708 473 3-Fluorobenzaldehyde

524.2668 474 4-Fluorobenzaldehyde

524.2665 475 3-Methoxybenzaldehyde

536.2888 476 3-Chlorobenzaldehyde

540.2387 477 1-Acetyl-4-piperidone

541.3156

Examples 478-503 Part A

A mixture of 2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol(prepared as described in Parts A-I of Example 2, 3.00 g, 10.5 mmol),1-bromo-3-chloropropane (1.82 g, 11.6 mmol), and cesium carbonate (10.27g, 31.53 mmol) in DMF (50 mL) was heated at 50° C. for 8 hours. Thereaction mixture was allowed to cool to room temperature and was stirredover a weekend. The slurry was poured into a solution of sodium chloride(200 g) in water (800 mL). After 6 hours, a precipitate had formed thatwas isolated by filtration. The precipitate was dissolved indichloromethane/chloroform, dried over magnesium sulfate, and filtered.The filtrate was used in the next reaction.

Part B

mCPBA (60% pure, 3.3 g, 11.5 mmol) was added in portions to the stirredfiltrate from Part A at room temperature. The reaction mixture wasstirred overnight. Concentrated ammonium hydroxide was added followed byp-toluenesulfonyl chloride (2.20 g, 11.5 mmol) in small portions. After2 hours, 1% aqueous sodium carbonate was added and the mixture wasstirred for 1 hour. The mixture was transferred to a separatory funneland the layers were separated. The organic phase was washed with 1%aqueous sodium carbonate (2×75 mL). The aqueous phases were combined andextracted with dichloromethane (1×100 mL). The organic layers were driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by chromatography on a HORIZONHPFC system (silica gel, gradient elution with 0-25% CMA in chloroform)to provide 2.4 g of8-(3-chloropropoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine.

Part C

An amine (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing8-(3-chloropropoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(38 mg, 0.10 mmol) and potassium carbonate (55 mg, 0.40 mmol) inN,N-dimethylacetamide (1 mL). The test tubes were capped and heated at70° C. for 16 hours, then at 85° C. for 6 hours. After the reactionmixtures were filtered, the solvent was removed by vacuumcentrifugation. The compounds were purified using the method describedin Examples 376-386. The table below shows the amine added to each testtube, the structure of the resulting compound, and the observed accuratemass for the isolated trifluoroacetate salt.

Examples 478-503

Measured Mass Example Reagent R (M + H) 478 None

377.1718 479 Piperidine

426.2886 480 3-Methylpiperidine

440.3015 481 1-Methylpiperazine

441.3000 482 3-(Dimethylamino)pyrrolidine

455.3170 483 N-Methylhomopiperazine

455.3141 484 2-Piperidinemethanol

456.2928 485 3-Azabicyclo[3.2.2]nonane

466.3185 486 Isonipecotamide

469.2953 487 Nipecotic acid

470.2718 488 N-(2-Hydroxyethyl)piperazine

471.3096 489 1,2,3,4-Tetrahydroisoquinoline

474.2879 490 Decahydroisoquinoline

480.3345 491 Decahydroquinoline

480.3343 492 1,3,3-Trimethyl-6- azabicyclo[3.2.1]octane

494.3507 493 4-(1-Pyrrolidinyl)-piperidine

495.3468 494 1-(2-Ethoxyethyl)piperazine

499.3405 495 2-Benzyl-2-imidazoline

501.3005 496 4-Phenylpiperidine

502.3179 497 1-Phenylpiperazine

503.3112 498 1-(2-Pyridyl)piperazine

504.3083 499 1-(4-Pyridyl)piperazine

504.3085 500 1-(2-Pyrimidyl)piperazine

505.3041 501 1-Cyclohexylpiperazine

509.3608 502 4-Piperidinopiperidine

509.3599 503 1-[2-(2- Hydroxyethoxy)ethyl]piperazine

515.3372

Examples 504-522 Part A

A mixture of4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-olhydrochloride (prepared using a modification on the procedure describedin Parts A and B of Example 51, 2.5 g, 7.4 mmol), 1-chloro-3-iodopropane(1.7 g, 8.2 mmol), and potassium carbonate (3.1 g, 22 mmol) in DMF (25mL) was stirred overnight, then triethylamine (2 mL) was added and thereaction mixture was heated to 70° C. for 8 hours. The mixture wasallowed to cool to room temperature and was stirred overnight. Themixture was poured into water (500 mL) and solid sodium hydroxide wasadded to adjust the mixture to pH 14. The mixture was extracted withchloroform (300 mL followed by 3×75 mL). The organic layers were thrownaway and the aqueous layer was adjusted to pH 10 with 10% aqueoushydrochloric acid. A precipitate formed and was isolated by filtration.The solid was subjected to the initial reaction conditions, and thistime methanol (25 mL) was added. After 3 hours at room temperature, thereaction mixture was heated at 90° C. and potassium carbonate (1 g) and1-chloro-3-bromopropane (1 mL) were added. After 3 hours, the reactionmixture was allowed to cool to room temperature, was filtered, and themethanol was removed under reduced pressure. The solution was pouredinto water (300 mL) and sodium chloride (200 g) was added, causing aprecipitate to form within 30 minutes. After 1 hour, the precipitate wasfiltered, dissolved in a minimal amount of chloroform, and purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-15% CMA in chloroform) to yield 900 mg of7-(3-chloropropoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine.

Part B

An amine (0.2 mmol, 2.0 equivalents) from the table below was added to atest tube containing7-(3-chloropropoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(38 mg, 0.10 mmol) and potassium carbonate (55 mg, 0.40 mmol) inN,N-dimethylacetamide (1 mL). The test tubes were capped and heated at90° C. for 10 hours. After the reaction mixtures were filtered, thesolvent was removed by vacuum centrifugation. The compounds werepurified using the method described in Examples 376-386. The table belowshows the amine added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 504-522

Measured Mass Example Reagent R (M + H) 504 Pyrrolidine

412.2679 505 Piperidine

426.2837 506 Morpholine

428.2685 507 4-Methylpiperidine

440.2992 508 Hexamethyleneimine

440.2983 509 1-Methylpiperazine

441.2997 510 4-Hydroxypiperidine

442.2843 511 Thiomorpholine

444.2455 512 3- (Dimethylamino) pyrrolidine

455.3094 513 N-Methylhomo- piperazine

455.3110 514 3- (Hydroxymethyl) piperidine

456.2964 515 Isonipecotamide

469.2969 516 Nipecotamide

469.2942 517 1-Acetylpiperazine

469.2945 518 4-Piperidineethanol

470.3167 519 N-(2- Hydroxyethyl) piperazine

471.3084 520 1,2,3,4- Tetrahydroiso- quinoline

474.2891 521 Decahydroiso- quinoline

480.3346 522 1-(2- Methoxyethyl) piperazine

485.3240

Examples 523-550 Part A

A solution of methoxyacetyl chloride (7.0 g, 64.5 mmol) indichloromethane (10 mL) was added dropwise to a stirred solution of6-(benzyloxy)-N⁴-propylquinoline-3,4-diamine (prepared as described inParts A-F of Example 2, approximately 58.7 mmol) in dichloromethane (300mL) at room temperature. After one hour, the solvent was removed underreduced pressure to yield a solid that was dissolved in ethanol (300mL). After 2% aqueous potassium carbonate (100 mL) was added, thereaction was heated at reflux for 30 minutes, then stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, then was partitioned between dichloromethane (300 mL)and 2% aqueous potassium carbonate (100 mL). The aqueous layer wasextracted with dichloromethane (3×100 mL). The organic layers werecombined, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by chromatography(silica gel, sequential elution with 4% then 7% methanol indichloromethane) to yield 18.2 g of a black solid that was used in thenext step.

Part B

mCPBA (60% pure, 15.7 g, 54.8 mmol) was added in small portions to asolution of the material from Part A (18.0 g, 49.8 mmol) indichloromethane (200 mL). After the reaction was complete, 2% aqueoussodium carbonate was added and the mixture was stirred vigorously. Anemulsion formed and chloroform and water were added. After two hours,the mixture was extracted multiple times with chloroform. The combinedorganic layers were dried over magnesium sulfate and filtered. Thefiltrate was used in the next step.

Part C

Trichloroacetyl isocyanate (6.5 mL, 54.8 mmol) was added slowly to thestirred filtrate from Part B. After 4 hours, additional isocyanate wasadded and the solution was stirred overnight. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved indichloromethane (400 mL). Concentrated ammonium hydroxide (20 mL) wasadded and the mixture was stirred at room temperature for 1 hour, then2% aqueous sodium carbonate (300 mL). The mixture was transferred to aseparatory funnel and the layers were separated. The aqueous layer, anemulsion, was extracted multiple times with chloroform. The organiclayers were combined, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to yield a dark brown solid that wasused in the next step.

Part D

A mixture of the material from Part C and 10% palladium on carbon inethanol/methanol (600 mL) was hydrogenated on a Parr apparatus at 30 psi(2.1×10⁵ Pa) for 72 hours. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The resulting solidwas treated with 2% aqueous sodium carbonate (300 mL), then concentratedhydrochloric acid was added to adjust to pH 1. After most of the solidhad dissolved, the pH of the solution was adjusted to pH 7 with sodiumcarbonate, causing a precipitate to form. The mixture was stirredovernight. The solid was isolated by filtration and used in the nextstep without purification.

Part E

A mixture of the material from Part D (2.5 g, 8.7 mmol),1-bromo-3-chloropropane (0.94 mL, 9.6 mmol), and cesium carbonate (5.7g, 17.4 mmol) in DMF (50 mL) was stirred overnight at room temperature.Additional cesium carbonate (1 equivalent) was added and the mixture washeated to 50° C. overnight. The mixture was allowed to cool to roomtemperature and was poured into a solution of sodium chloride (250 g) inwater (800 mL). After 20 minutes, a dark precipitate formed and wasisolated by filtration. The solid was dissolved in chloroform, driedover magnesium sulfate, filtered, and concentrated. The crude productwas purified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 0-30% of a 20% methanol in dichloromethanesolution in dichloromethane) to yield 1.18 g of8-(3-chloropropoxy)-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-aminethat contained some impurities.

Part F

An amine (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing8-(3-chloropropoxy)-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(36 mg, 0.10 mmol) and potassium carbonate (55 mg, 0.40 mmol) inN,N-dimethylacetamide (1 mL). The test tubes were capped and heated at90° C. for 16 hours. After the reaction mixtures were filtered, thesolvent was removed by vacuum centrifugation. The compounds werepurified using the method described in Examples 376-386. The table belowshows the amine added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 523-550

Measured Mass Example Reagent R (M + H) 523 None

363.1563 524 Pyrrolidine

398.2574 525 Piperidine

412.2709 526 Morpholine

414.2532 527 Thiazolidine

416.2142 528 3-Methylpiperidine

426.2871 529 4-Methylpiperidine

426.2856 530 Hexamethyleneimine

426.2835 531 1-Methylpiperazine

427.2804 532 3-Hydroxypiperidine

428.2652 533 4-Hydroxypiperidine

428.2681 534 Thiomopholine

430.2297 535 3- (Dimethylamino) pyrrolidine

441.2975 536 N-Ethylpiperazine

441.2952 537 N- Methylhomopiperazine

441.2940 538 2- Piperidinemethanol

442.2831 539 3- (Hydroxymethyl) piperidine

442.2821 540 4- (Hydroxymethyl) piperidine

442.2847 541 Isonipecotamide

455.2816 542 1-Acetylpiperazine

455.2813 543 Isonipecotic acid

456.2655 544 Nipecotic acid

456.2640 545 2-Piperidineethanol

456.3009 546 4-Piperidineethanol

456.3000 547 N-(2- Hydroxyethyl) piperazine

457.2939 548 2-Benzyl-2- imidazoline

487.2834 549 4-Phenylpiperazine

489.3026 550 1-(2-Pyrimidyl) piperazine

491.2915

Example 551 tert-Butyl2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate

Part A

Ammonium hydroxide (1 L) was added to a solution of methyltetrahydro-2H-pyran-4-carboxylate (20 mL, 150 mmol) in methanol (500mL), and the reaction was stirred overnight at ambient temperature.Additional ammonium hydroxide (500 mL) was added, and the reaction wasstirred for four additional days. The methanol was removed under reducedpressure. Solid sodium chloride was added to the aqueous layer, whichwas extracted with chloroform (3×150 mL). The combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure to provide 11.4 g of tetrahydro-2H-pyran-4-carboxamide as awhite solid.

Part B

A solution of tetrahydro-2H-pyran-4-carboxamide (11.4 g, 88.3 mmol) inTHF (441 mL) was cooled to 0° C. Lithium aluminum hydride (10.0 g, 265mmol) was added in six portions over a period of ten minutes. Thereaction flask was purged with nitrogen between the additions. When thereaction mixture was no longer bubbling, it was heated at reflux for sixhours. The reaction was then cooled to 0° C., and ethyl acetate wasadded dropwise until bubbling ceased. Methanol was then added dropwiseuntil bubbling ceased. Water (10 mL), 15% aqueous sodium hydroxide (10mL), and water (30 mL) were sequentially added. The organic fraction wasdecanted off, and the remaining gray solid was washed with chloroform.The combined organic fractions were dried over sodium sulfate, filtered,and concentrated under reduced pressure to providetetrahydro-2H-pyran-4-ylmethylamine.

Part C

7-(Benzyloxy)-3-nitroquinolin-4-ol (12.3 g, 41.6 mmol) was slurried inDMF (83 mL). Phosphorous oxychloride (4.2 mL, 45 mmol) was added in oneportion and the mixture was heated at 100° C. for 5 minutes. Thesolution was allowed to cool to 40° C. and was then poured into icewater (total volume 400 mL) resulting in a tan precipitate. Theprecipitate was filtered and washed with water. After drying, the solidwas dissolved in dichloromethane and the residual water was separated.The organic fraction was dried over anhydrous sodium sulfate andanhydrous magnesium sulfate (about a 50/50 mixture). The organicfraction was filtered into a reaction flask (total volume of organicwith 7-(benzyloxy)-3-chloro-4-nitroquinoline is about 425 mL). The flaskwas cooled to 8° C. and triethylamine (11.6 mL, 83.0 mmol) was added.(Tetrahydro-2H-pyran-4-yl)methylamine (6.0 g, 52 mmol) indichloromethane (50 mL) was added dropwise to the mixture. The coolingbath was removed and the reaction was stirred for 16 hours. Water (200mL) was added followed by stirring for 30 minutes. The layers wereseparated and the organic fraction was sequentially washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. Recrystallization from2-propanol afforded 14.1 g of7-(benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amineas a yellow powder.

Part D

7-(Benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine(14.1 g, 35.6 mmol) and 5% platinum on carbon (2.0 g) were added to aParr vessel. The solids were covered with acetonitrile (200 mL) andplaced on a hydrogenator. The vessel was degassed three times, thencharged with 50 psi (3.4×10⁵ Pa) hydrogen and allowed to shake for 3hours, replenishing the hydrogen as needed. After 6 hours, the catalystwas removed by filtration through CELITE filter agent. The CELITE waswashed with acetonitrile until the filtrate ran clear (˜300 mL). Thesolvent was evaporated to ½ volume under reduced pressure and cooled to8° C. Propionyl chloride (3.15 mL, 35.6 mmol) was added dropwise to thesolution over 3 minutes. The cooling bath was removed and the reactionwas stirred for 16 hours. The resulting precipitate was filtered andwashed with acetonitrile. Drying under vacuum for 1 hour afforded 14.2 gofN-{7-(benzyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}propanamidedihydrochloride as a tan solid.

Part E

N-{7-(Benzyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}propanamidedihydrochloride (14.2 g, 31.1 mmol) was slurried in ethanol (150 mL) anddiluted with water (50 mL). Potassium carbonate (12.3 g, 89 mmol) inwater (15 mL) was added and the reaction was stirred until dissolution(˜30 minutes). The reaction was then heated to 60° C. for 16 hours. Theethanol was evaporated under reduced pressure and the remaining waterwas extracted with dichloromethane. The organic fraction wassequentially washed with water, followed by saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered andconcentrated. Recrystallization from acetonitrile afforded 8.4 g of7-(benzyloxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolineas a tan powder.

Part F

7-(Benzyloxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline(8.3 g, 20.7 mmol) was added to a Parr vessel containing 10% palladiumon carbon (1.5 g) wetted with acetonitrile. Methanol (160 mL) was addedand the vessel was placed on the hydrogenator. The vessel was degassedthree times and charged with 50 psi (3.4×10⁵ Pa) hydrogen. The vesselwas allowed to shake for 16 hours, replenishing the hydrogen as needed.The catalyst was removed by filtration through glass fiber filter paper.The catalyst was washed with 3:1 chloroform/methanol. The filtrates werecombined. Evaporation under reduced pressure afforded 6.1 g of2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-olas a gray solid.

Part G

The material was prepared using the general method described in Part Aof Example 390. tert-Butyl 2-iodoethylcarbamate (5.26 g, 19.4 mmol addedover 24 hours, then 1 g, 3.70 mmol after 72 hours), was used in lieu oft-butyl 3-iodopropylcarbamate. Purification via chromatography on aHORIZON HPFC system (gradient elution with 2-25% CMA in chloroform),followed by recrystallization from acetonitrile afforded 2.34 g oftert-butyl2-{[2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas white flakes.

Part H

tert-Butyl2-{[2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(2.3 g, 5.06 mmol) was slurried in ethyl acetate (20 mL). 32% Peraceticacid in acetic acid (1.06 mL, 5.06 mmol) was added in one portion andthe reaction was heated to 50° C. for 2 hours. Another 0.250 mL (1.19mmol) peracetic acid solution was added and the reaction was stirred for1 additional hour. Sodium metabisulfite (1.2 g, 6.33 mmol) in water (2.5mL) was added over 3 minutes and the reaction was stirred for 30minutes. The heat was removed and the reaction was brought to pH 10 withsaturated aqueous sodium carbonate (˜10 mL). The milky slurry was cooledin an ice bath and subsequently filtered. The solid was washed withwater and dried for 1 hour. Roughly 2.0 g of tert-butyl2-{[2-ethyl-5-oxido-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamatewas isolated as an off-white solid with water still remaining.

Part I

tert-Butyl2-{[2-ethyl-5-oxido-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(wet from above) was slurried in dichloromethane (25 mL) and ammoniumhydroxide (25 mL). p-Toluenesulfonyl chloride (0.810 g, 4.25 mmol) wasadded in one portion and the reaction was stirred for 16 hours. Thelayers were separated and the aqueous fraction was extracted withdichloromethane. The combined organic fractions were washed with water,then saturated aqueous sodium chloride. The organic fraction was driedover anhydrous sodium sulfate, filtered and concentrated. The materialwas purified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 2-20% CMA in chloroform) to afford 1.8 g oftert-butyl2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas a white foam. Recrystallization from acetonitrile of a small portionprovided an analytical sample as a white solid, mp 200-201° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (d, J=9.1 Hz, 1H), 7.05 (d, J=2.7 Hz,1H), 7.02 (t, J=5.3 Hz, 1H), 6.90 (dd, J=9.0, 2.6 Hz, 1H), 6.38 (s, 2H),4.39-4.36 (m, 2H), 4.04 (t, J=5.8 Hz, 2H), 3.84-3.79 (m, 2H), 3.34 (q,J=5.7 Hz, 2H), 3.21-3.08 (m, 2H), 2.91 (q, J=7.4 Hz, 2H), 2.14-1.97 (m,1H), 1.54-1.36 (m, 4H), 1.39 (s, 9H), 1.36 (t, J=7.4 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 155.0, 155.7, 153.7, 152.0, 146.6, 132.9,125.1, 121.2, 111.5, 109.1, 108.2, 77.7, 66.6, 66.2, 49.6, 35.7, 29.6,28.2, 20.1, 12.1;

MS (APCI) m/z 470.3 (M+H)⁺;

Anal. calcd for C₂₅H₃₅N₅O₄: C, 63.95; H, 7.51; N, 14.91. Found: C,63.80; H, 7.54; N, 15.06.

Example 5527-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride

tert-Butyl2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(1.8 g, 3.83 mmol) was added to 4.0M ethanolic hydrogen chloride (13 mL)and the reaction was heated to 65° C. for 1 hour. The milky slurrysolidified after 20 minutes. Ethanol (10 mL) was added to loosen thesolid. After 1 hour, the heat was removed and the reaction was allowedto cool to ambient temperature. Filtration afforded 1.3 g of7-(2-aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride as a white solid, mp 238° C., decomposition.

¹H NMR (300 MHz, DMSO-d₆) δ 14.24 (s, 1H), 8.75 (br s, 2H), 8.43 (br s,3H), 8.20 (d, J=9.2 Hz, 1H), 7.36 (d, J=2.5 Hz, 1H), 7.26 (dd, J=9.1,2.4 Hz, 1H), 4.50-4.47 (m, 2H), 4.36 (t, J=4.9 Hz, 2H), 3.85-3.81 (m,2H), 3.36-3.23 (m, 2H), 3.22-3.07 (m, 2H), 2.99 (q, J=7.4 Hz, 2H),2.13-1.94 (m, 1H), 1.59-1.40 (m, 4H), 1.40 (t, J=7.4 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 158.3, 157.4, 148.9, 135.5, 135.3, 123.5,122.9, 114.0, 106.9, 102.1, 66.5, 64.7, 49.9, 38.1, 35.6, 29.4, 20.2,11.6;

MS (ESI) m/z 370.2 (M+H)⁺.

Example 5532-Ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

mCPBA (2.0 g of 60%, 6.97 mmol) was added to a solution of7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline(2.8 g, 6.97 mmol) in chloroform (50 mL). After 30 minutes an additionalequivalent of mCPBA was added and the reaction mixture was stirred foran additional hour. Ammonium hydroxide (20 mL) was added and thereaction mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride(1.33 g, 6.97 mmol) was added in a single portion and the reactionmixture was stirred for 16 hours. The layers were separated and theaqueous layer was extracted with dichloromethane (2×100 mL). Theorganics were combined, washed with water and brine, dried over sodiumsulfate, filtered, and then concentrated under reduced pressure. Theresidue was purified by chromatography on a HORIZON HPFC system (40+Mcartridge eluting with a gradient of 2 to 25% CMA in chloroform). Theresidue was combined with acetonitrile and allowed to stand overnight. Asolid was isolated by filtration and rinsed with acetonitrile to provide1.96 g of7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a tan solid.

Part B

A mixture of7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.76 g, 4.23 mmol), palladium on carbon (1 g), and ethanol (50 mL) wasshaken under hydrogen pressure (50 psi, 3.4×10⁵ Pa) on a Parr apparatusovernight. The reaction mixture was diluted with dichloromethane (75 mL)and then filtered through a layer of CELITE filter agent. The filtercake was rinsed with 25% methanol in chloroform (400 mL). The combinedfiltrates were concentrated under reduced pressure to provide a whitesolid. This material was slurried with methanol, isolated by filtration,and dried under vacuum to provide 0.98 g of4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol.

Part C

A mixture of4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol(500 mg, 1.53 mmol), 2-bromo-1-(morpholin-4-yl)ethanone (351 mg, 1.69mmol), cesium carbonate (1.5 g, 4.59 mmol) and anhydrous DMF was heatedat 70° C. overnight. The reaction mixture was cooled, poured into water(350 mL), and then extracted with dichloromethane (2×100 mL). Thecombined organics were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure. The residue was dissolved indichloromethane and filtered. The filtrate was purified bychromatography on a HORIZON HPFC system (eluting with a gradient of 0 to8% methanol in dichloromethane). The product was recrystallized fromacetonitrile to provide 362 mg of2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, mp 245-247° C. Anal. calcd for C₂₄H₃₁N₅O₄: C, 63.56;H, 6.89; N, 15.44. Found: C, 63.20; H, 6.78; N, 15.31.

Example 5542-Methoxymethyl-8-(3-morpholin-4-ylpropoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

Cesium carbonate (5.7 g, 17.4 mmol, 2 eq) was added to a mixture of8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(2.5 g, 8.7 mmol, 1 eq), prepared as described in Examples 523-550 PartsA-D, 1-bromo-3-chloropropane (0.94 mL, 9.6 mmol, 1.1 eq), and 50 mL ofN,N-dimethylformamide (DMF). The reaction mixture was stirred overnight.Analysis by HPLC indicated the reaction was incomplete. Additionalcesium carbonate (2.85 g) was added to the reaction mixture and themixture was heated to 50° C. overnight. Analysis by HPLC indicated thereaction was complete and the reaction mixture was poured into a brinesolution (250 g of sodium chloride in 800 mL of deionized water). After20 minutes, a dark brown/black material precipitated and was filtered.The solid material was dissolved in chloroform, dried over magnesiumsulfate, and purified by chromatography on a HORIZON HPFC system(eluting with a gradient of methanol/dichloromethane (20:80) indichloromethane from 0:100 to 30:70). The combined fractions wereconcentrated, dissolved in dichloromethane and methanol, andconcentrated under reduced pressure to yield 1.18 g of8-(3-chloropropoxy)-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine.

Part B

Potassium carbonate (530 mg, 3.84 mmol), morpholine (92 mg, 1.06 mmol),and8-(3-chloropropoxy)-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(350 mg, 0.96 mmol) were added to 15 mL of DMF and heated to 50° C. for18 hours. Analysis by LC/MS indicated the presence of two peaks and thereaction mixture was cooled and poured into 500 mL of deionized water.After three hours, no precipitation was observed. Sodium chloride (250g) was added to the mixture and the mixture was stirred vigorouslyovernight. The precipitate was collected by filtration, dissolved indichloromethane, and purified by chromatography on a HORIZON HPFC system(eluting with a gradient of methanol/dichloromethane (20:80) indichloromethane from 0:100 to 40:60). The resulting material wasconcentrated under reduced pressure, crystallized from acetonitrile, anddried under high vacuum to yield 36 mg of2-methoxymethyl-8-(3-morpholin-4-ylpropoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas tan crystals, mp 193-196° C. Anal. calcd for C₂₂H₃₁N₅O₃: C, 63.90; H,7.56; N, 16.94. Found: C, 63.58; H, 7.76; N, 17.28.

Example 5553-{[4-Amino-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propylmorpholine-4-carboxylate

A second product was isolated after chromatographic purification ofExample 554; 92 mg of3-{[4-amino-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propylmorpholine-4-carboxylate was isolated as pale yellow crystals, mp173-174° C.

Anal. calcd for C₂₃H₃₁N₅O₅: C, 60.38; H, 6.83; N, 15.31. Found: C,60.12; H, 7.09; N, 15.44.

Example 5562-(Methoxymethyl)-8-(2-oxo-2-thiomorpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Cesium carbonate (1.7 g, 5.22 mmol, 3 eq) was added to a mixture of4-(bromoacetyl)thiomorpholine (468 mg, 2.09 mmol, 1.2 eq, preparedaccording to the method described in Part C of Example 30) and8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(500 mg, 1.74 mmol, 1.0 eq) in 20 mL of DMF. The reaction mixture washeated to 70° C. and maintained for 14 hours. The reaction mixture wasthen cooled to ambient temperature, filtered, diluted with 50 mL ofdichloromethane, concentrated under reduced pressure, and filtered toafford crude material. The crude material was purified by chromatographyon a HORIZON HPFC system (eluting with a gradient ofmethanol/dichloromethane (20:80) in dichloromethane from 0:100 to40:60), concentrated under reduced pressure, and crystallized fromacetonitrile to afford 231 mg of2-(methoxymethyl)-8-(2-oxo-2-thiomorpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off white solid, mp 214-216° C.

Anal. calcd for C₂₁H₂₇N₅O₃S: C, 58.72; H, 6.34; N, 16.30. Found: C,58.60; H, 6.48; N, 16.41.

Example 5572-(Methoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Cesium carbonate (1.7 g, 5.25 mmol, 3 eq) was added to a mixture of2-bromo-1-morpholin-4-yl-ethanone (400 mg, 1.92 mmol, 1.1 eq),8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(500 mg, 1.75 mmol, 1.0 eq), and anhydrous DMF. The reaction mixture washeated to 70° C. and maintained overnight. The reaction mixture was thencooled to ambient temperature, filtered, and concentrated under reducedpressure to yield a dark oil. The dark oil was dissolved indichloromethane, filtered, purified by chromatography on a HORIZON HPFCsystem (eluting with a gradient of methanol/dichloromethane (20:80) indichloromethane from 0:100 to 40:60), and crystallized from acetonitrileto afford 356 mg of2-(methoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off white powder, mp 201-204° C.

Anal. calcd for C₂₁H₂₇N₅O₄: C, 61.00; H, 6.58; N, 16.94. Found: C,60.82; H, 6.51; N, 16.86.

Example 5582-Methoxymethyl-8-(1-methylpiperidin-3-ylmethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Potassium carbonate (1.48 g, 10.75 mmol),3-chloromethyl-1-methyl-piperidine hydrochloride (483 mg, 2.62 mmol),sodium iodide (100 mg, 0.66 mmol), and8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(500 mg, 1.75 mmol) were combined in acetone and heated at refluxovernight. No desired product was detected and the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure,dissolved in DMF, and heated at 90° C. overnight. The reaction mixturewas then cooled to ambient temperature, filtered, and concentrated underreduced pressure to provide a dark oil. The oil was dissolved indichloromethane, filtered, purified by chromatography on a HORIZON HPFCsystem (eluted with a gradient of CMA: chloroform from 0:100 to 35:65),and crystallized from acetonitrile to afford 160 mg of2-methoxymethyl-8-(1-methyl-piperidin-3-yl-methoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder, mp 194-196° C.

Anal. calcd for C₂₂H₃₁N₅O₂: C, 66.47; H, 7.86; N, 17.62. Found: C,66.27; H, 8.15; N, 17.74.

Example 5592-Methoxymethyl-8-(2-piperidin-1-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Potassium carbonate (1.48 g, 10.75 mmol), N-(2-chloroethyl)-piperidinehydrochloride (483 mg, 2.62 mmol), sodium iodide (100 mg, 0.66 mmol),and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(500 mg, 1.75 mmol) were combined in acetone as a slurry and heated atreflux overnight. The reaction mixture was cooled to ambient temperatureand filtered. The filter cake was washed with acetone and the combinedfiltrate was concentrated under reduced pressure to afford a solid. Thesolid material was dissolved in dichloromethane and purified bychromatography on a HORIZON HPFC system (eluting with a gradient ofCMA:chloroform from 0:100 to 40:60). The resulting material wasconcentrated under reduced pressure and crystallized from acetonitrileto afford 175 mg of2-methoxymethyl-8-(2-piperidin-1-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas tan crystals, mp 160-162° C. Anal. calcd for C₂₂H₃₁N₅O₂.0.33CH₃CN.0.33 H₂O: C, 65.18; H, 7.90; N, 17.82. Found: C, 65.18; H, 8.05;N, 18.10.

Example 5607-[(1-Acetylpiperidin-4-yl)oxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Aceticanhydride (0.122 mL, 1.3 mmol) was added dropwise to the slurry and themixture was stirred for 36 hours. Saturated aqueous sodium carbonate (5mL) was added and the reaction was stirred for 1 hour. The layers wereseparated and the organic fraction was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution with 1-22% CMA inchloroform). The resulting amorphous solid was triturated with boilingacetonitrile. Filtration afforded 0.270 g of7-[(1-acetylpiperidin-4-yl)oxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid, mp 178-179.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.91 (d, J=9.0 Hz, 1H), 7.13 (d, J=2.6 Hz,1H), 6.96 (dd, J=9.0, 2.6 Hz, 1H), 6.52 (s, 2H), 4.75 (s, 2H), 4.75-4.66(m, 1H), 4.52-4.41 (m, 2H), 3.98-3.82 (m, 1H), 3.78-3.64 (m, 1H), 3.55(q, J=7.0 Hz, 2H), 3.44-3.16 (m, 2H), 2.09-1.77 (m, 4H), 2.03 (s, 3H),1.74-1.45 (m, 2H), 1.16 (t, J=7.0 Hz, 3H), 1.00 (t, J=7.3 Hz, 3H);

MS (APCI) m/z 426.2 (M+H)⁺;

Anal. calcd for C₂₃H₃₁N₅O₃: C, 64.92; H, 7.34; N, 16.46. Found: C,64.76; H, 7.64; N, 16.60.

Example 5612-(Ethoxymethyl)-7-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

The general method described in Example 560 was followed usingmethanesulfonyl chloride (0.100 mL, 1.3 mmol) in lieu of aceticanhydride. The reaction time was reduced to 2 hours. Filtration fromacetonitrile afforded 0.381 g of2-(ethoxymethyl)-7-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas a pale yellow solid, mp 215-217° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (d, J=9.0 Hz, 1H), 7.13 (d, J=2.5 Hz,1H), 6.97 (dd, J=9.0, 2.5 Hz, 1H), 6.53 (s, 2H), 4.75 (s, 2H), 4.72-4.62(m, 1H), 4.53-4.41 (m, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.46-3.32 (m, 2H),3.23-3.08 (m, 2H), 2.92 (s, 3H), 2.14-1.99 (m, 2H), 1.94-1.71 (m, 4H),1.16 (t, J=7.0 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 155.7, 152.3, 148.1, 147.0, 133.3, 125.0,121.5, 112.5, 110.0, 109.0, 70.7, 65.3, 64.2, 46.7, 42.6, 34.4, 29.8,23.0, 14.9, 10.7;

MS (APCI) m/z 462.3 (M+H)⁺;

Anal. calcd for C₂₂H₃₁N₅O₄S: C, 57.25; H, 6.77; N, 15.17; % S, 6.95.Found: C, 57.14; H, 7.04; N, 15.48; % S, 6.77.

Example 562 tert-Butyl2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate

A modification of the methods described in Parts A-I of Example 2 wasused to prepare2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol,with 3-benzyloxyaniline and 1-amino-2-methylpropan-2-ol used in lieu of4-benzyloxyaniline and propylamine, respectively.

Part A

2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol(4.0 g, 12.7 mmol) and cesium carbonate (6.20 g, 19.0 mmol) wereslurried in DMF (100 mL). tert-Butyl 2-iodoethylcarbamate (4.12 g, 15.2mmol) in DMF (27 mL) was added, and the mixture was heated to 65° C.under nitrogen. After 15 hours, the DMF was removed under reducedpressure. The residue was taken up in dichloromethane and washedrepeatedly with water. The organic layer was dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by chromatography on a HORIZON HPFC system (silica gel, 2-30%CMA in chloroform) to afford, after evaporation of the solvent, 2.9 g oftert-butyl2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas a tan foam.

Part B

tert-Butyl2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(2.9 g, 6.32 mmol) was dissolved in ethyl acetate (25 mL). 32% Peraceticacid in acetic acid (1.99 mL, 9.48 mmol) was added to the solution andthe mixture was heated to 50° C. for 2 hours. Another 0.5 mL of theperacetic acid solution (2.37 mmol) was added and the reaction wasstirred for 1 hour. A solution of sodium metabisulfite in water (1.5 gin 3.0 mL) was added in two portions and the reaction mixture wasstirred for 10 minutes. The heat was then removed and the solution wasbrought to pH≈10 with saturated aqueous sodium carbonate (˜15 mL). Theresulting precipitate was filtered, washed with ethyl acetate (10 mL)and water (10 mL), and dried under vacuum to afford 2.8 g of tert-butyl2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas a white paper-like solid with some water remaining.

Part C

tert-Butyl2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(2.8 g, 5.05 mmol) was dissolved in dichloromethane (35 mL) and ammoniumhydroxide (25 mL). p-Toluenesulfonyl chloride (0.962 g, 5.05 mmol) wasadded in one portion and the reaction was stirred for 16 hours. Thelayers were separated and the aqueous fraction was extracted withdichloromethane. The organics were combined and evaporated under reducedpressure. The residue was purified by chromatography on a HORIZON HPFCsystem (silica gel, 2-25% CMA in chloroform) to provide 1.95 g oftert-butyl2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamateas white crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=9.1 Hz, 1H), 7.06-6.98 (m, 1H),7.02 (d, J=2.6 Hz, 1H), 6.84 (dd, J=9.0, 2.6 Hz, 1H), 6.49 (s, 2H),5.01-4.73 (m, 1H), 4.86 (s, 2H), 4.61 (br s, 2H), 4.04 (t, J=5.8 Hz,2H), 3.50 (q, J=7.0 Hz, 2H), 3.39-3.27 (m, 2H), 1.39 (s, 9H), 1.16 (brs, 6H), 1.13 (t, J=7.0 Hz, 3H);

MS (ESI) m/z 474.3 (M+H)⁺.

Example 563 tert-Butyl4-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate

Part A

2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol(3.31 g, 10.5 mmol), triphenylphosphine (3.43 g, 13.1 mmol) andtert-butyl 4-hydroxypiperidine-1-carboxylate (2.64 g, 13.1 mmol) wereslurried in THF (105 mL) and cooled with an ice/water bath. Diisopropylazodicarboxylate (2.58 mL, 13.1 mmol) was added dropwise. The coolingbath was removed and the reaction was stirred for 16 hours. The solventwas removed under reduced pressure and the residue was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 1-28% CMA in chloroform) to afford 3.32 g of tert-butyl4-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas a tan foam.

Part B

To a stirring solution of tert-butyl4-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(3.32 g, 6.66 mmol) in chloroform (70 mL) was added3-chloroperoxybenzoic acid (2.29 g, 6.66 mmol, based on 50% purity).After 30 minutes, concentrated ammonium hydroxide (35 mL) was added andthe reaction was stirred for 15 minutes. p-Toluenesulfonyl chloride(1.27 g, 6.66 mmol) was added in one portion and stirring was continuedfor 16 additional hours. The layers were separated and the organicfraction was washed with water, then saturated aqueous sodium chloride.The organic fraction was evaporated under reduced pressure and theresidue was purified by chromatography on a HORIZON HPFC system (silicagel, gradient elution with 2-28% CMA in chloroform), followed byrecrystallization from acetonitrile to afford 0.630 g of tert-butyl4-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylateas a tan crystalline solid, mp 214-215° C., decomposition.

¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=9.1 Hz, 1H), 7.07 (d, J=2.6 Hz,1H), 6.86 (dd, J=9.1, 2.6 Hz, 1H), 6.48 (s, 2H), 5.04-4.74 (m, 1H), 4.86(s, 2H), 4.70-4.53 (m, 3H), 3.79-3.64 (m, 2H), 3.50 (q, J=7.0 Hz, 2H),3.28-3.12 (m, 2H), 2.04-1.88 (m, 2H), 1.67-1.47 (m, 2H), 1.41 (s, 9H),1.16 (br s, 6H), 1.13 (t, J=7.0 Hz, 3H);

MS (ESI) m/z 514.4 (M+H)⁺;

Anal. calcd for C₂₇H₃₉N₅O₅: C, 63.14; H, 7.65; N, 13.63. Found: C,62.79; H, 7.77; N, 13.41.

Example 5641-[4-Amino-7-(1,3-dioxolan-2-ylmethoxy)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[7-Benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olwas prepared according to a modification of the methods described inParts A-H of Example 2, with 3-benzyloxyaniline,1-amino-2-methylpropan-2-ol, and 3-methoxypropanoyl chloride used inlieu of 4-benzyloxyaniline, propylamine, and ethoxyacetyl chloride,respectively. The general methods described in Parts H through J ofExample 1 were used to convert[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olto4-amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol.A mixture of4-amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol(375 mg, 1.13 mmol), 2-bromomethyl-1,3-dioxolane (208 mg, 1.24 mmol) andpotassium carbonate (312 mg, 2.26 mmol) in DMF (15 mL) was heated at 70°C. overnight. The temperature was increased to 130° C. and additional2-bromomethyl-1,3-dioxolane and potassium carbonate were added over 3days. The reaction mixture was allowed to cool to room temperature, thenwas filtered to remove the solids. The filtrate was concentrated underreduced pressure and the residue was slurried in dichloromethane. Again,the solids were removed by filtration and the filtrate was concentratedunder reduced pressure. Purification by chromatography on a HORIZON HPFCsystem (silica gel, gradient elution with 0-35% methanol/dichloromethane(20:80) in dichloromethane) followed by recrystallization fromacetontrile provide 20 mg of1-[4-amino-7-(1,3-dioxolan-2-ylmethoxy)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas off white crystals, mp 131.0-136.0° C.

MS (APCI) m/z 417 (M+H)⁺;

Anal. calcd for C₂₁H₂₈N₄O₅.0.58 H₂O: C, 59.08; H, 6.89; N, 13.12. Found:C, 59.08; H, 7.00; N, 13.18.

Example 5658-[2-(1,1-Dioxidothiomorpholin-4-yl)-2-oxoethoxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

The synthesis of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described inParts A-I of Example 2. A mixture of2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (1.0 g, 3.5mmol), 4-(bromoacetyl)thiomorpholine (941 mg, 4.2 mmol, prepared fromthiomorpholine according to the method described in Part C of Example30), and cesium carbonate (3.4 g, 10.5 mmol) in DMF was heated at 70° C.for 6 hours, then at 50° C. overnight. The reaction was allowed to coolto room temperature and the solids were removed by filtration. Thefiltrate was concentrated under reduced pressure and the residue wastreated with dichloromethane. More solids were removed by filtration.The filtrate was used in the next step.

Part B

The filtrate from Part A was diluted with dichloromethane (400 mL).mCPBA (60% pure, 3.50 g, 12.3 mmol) was added in portions to the stirredsolution. After 5 hours, concentrated ammonium hydroxide (200 mL) wasadded in two portions. The mixture was stirred vigorously asp-toluenesulfonyl chloride (805 mg, 4.2 mmol) was added over 10 minutes.After 1 hour, the mixture was transferred to a separatory funnel and thelayers were separated. The organic layer was washed with 1% aqueoussodium carbonate (2×100 mL). The aqueous layers were combined andextracted with chloroform (6×100 mL). The organic layers were combined,dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by chromatography on a HORIZONHPFC system (silica gel, gradient elution with 0-35% CMA in chloroform)then recrystallized from acetonitrile to provide 80 mg of8-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethoxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off white solid, mp 223.0-225.0° C.

MS (APCI) m/z 476 (M+H)⁺;

Anal. calcd for C₂₂H₂₉N₅O₅S: C, 55.56; H, 6.15; N, 14.73. Found: C,55.45; H, 6.14; N, 15.08.

Example 5662-(Ethoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

mCPBA (60% pure, 27.5 g, 95.9 mmol) was added in small portions over aperiod of 20 minutes to8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinoline (30.0g, 79.9 mmol, prepared in Parts A through H of Example 2) indichloromethane (400 mL). After the reaction was stirred for two hours,it was washed with 1% aqueous sodium carbonate (3×100 mL). The combinedaqueous washings were extracted with chloroform (200 mL), and thecombined organic fractions were dried over magnesium sulfate andfiltered. Trichloroacetyl isocyanate (18.0 g, 95.9 mmol) was addeddropwise to the filtrate, and then the reaction was stirred overnight atambient temperature. Concentrated ammonium hydroxide (100 mL) was slowlyadded, and the mixture was stirred at ambient temperature for 30minutes. The organic layer was separated and washed with 1% aqueoussodium carbonate (2×100 mL). The combined aqueous fractions wereextracted with chloroform (3×75 mL). The organic fractions werecombined, dried over magnesium sulfate, filtered, and concentrated underreduced pressure to yield a dark semi-solid. The crude product waspurified on silica gel (1 kg, eluting sequentially with 2% methanol inchloroform and 5% methanol in chloroform) to provide 22 g of8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid.

Part B

A dispersion of8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(22.0 g, 56.3 mmol) and 10% palladium on carbon (7.5 g) in 50:50ethanol/methanol (300 mL) was shaken under hydrogen pressure on a Parrapparatus at 50 psi (3.4×10⁵ Pa) for three days. The reaction mixturewas filtered to remove the catalyst, which was washed with hotethanol/methanol (3 L). The filtrate was concentrated under reducedpressure. The resulting solid was triturated with methanol and isolatedby filtration to provide 10.4 g of4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol as anoff-white solid.

Part C

Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of2-bromo-1-morpholin-4-yl-ethanone (414 mg, 1.99 mmol),4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500mg, 1.66 mmol), and anhydrous DMF (20 mL). The reaction mixture washeated at 75° C. overnight, allowed to cool, and poured into deionizedwater (300 mL). The resulting mixture was stirred for 30 minutes andthen extracted with chloroform (3×100 mL). The combined organicfractions were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The resulting solid was purified bychromatography on a HORIZON HPFC system (silica cartridge, eluting witha gradient of 0-35% methanol/dichloromethane (10:90) indichloromethane). The resulting solid was recrystallized fromacetonitrile to yield 333 mg of2-(ethoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid, mp 196-197° C. Anal. calcd for C₂₂H₂₉N₅O₄: C,61.81; H, 6.84; N, 16.38. Found: C, 61.72; H, 6.86; N, 16.62.

Example 5672-(Methoxymethyl)-8-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

Potassium carbonate (1.48 g, 10.75 mmol),2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (483 mg, 2.62 mmol),sodium iodide (100 mg, 0.66 mmol), and8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(500 mg, 1.75 mmol) were combined in acetone and heated at refluxovernight. Additional 2-(2-chloroethyl)-1-methylpyrrolidinehydrochloride and potassium carbonate were added, and the reaction washeated at reflux overnight. The reaction mixture was then cooled toambient temperature, filtered, and concentrated under reduced pressure.The residue was purified by chromatography on a HORIZON HPFC system(silica cartridge, eluting with a gradient of CMA: chloroform from 0:100to 25:75) followed by recrystallization from acetonitrile to afford 105mg of2-methoxymethyl-8-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid, mp 155-157° C. Anal. calcd forC₂₂H₃₁N₅O₂.0.25H₂O: C, 65.66; H, 7.90; N, 17.40. Found: C, 65.66; H,8.24; N, 17.26.

Example 5682-Ethyl-7-(2-morpholin-4-ylethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine

Cesium carbonate (1.41 g, 4.32 mmol) was added to a solution of4-(2-chloroethyl)morpholine hydrochloride (348 mg, 1.87 mmol) and4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol(471 mg, 1.44 mmol, prepared in Parts A and B of Example 553) inanhydrous DMF (25 mL). The reaction mixture was heated at 75° C.overnight, allowed to cool, and poured into 1% aqueous sodium carbonate(300 mL). The resulting mixture was stirred for two hours and thenextracted with chloroform (4×100 mL). The combined organic fractionswere dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting solid was purified by chromatography ona HORIZON HPFC system (silica cartridge, eluting with a gradient of0-40% methanol/dichloromethane (20:80) in dichloromethane). Theresulting solid was recrystallized from acetonitrile and dried undervacuum to yield 393 mg of2-ethyl-7-(2-morpholin-4-ylethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid, mp 230-232° C. Anal. calcd for C₂₄H₃₃N₅O₃: C,65.58; H, 7.57; N, 15.93. Found: C, 65.48; H, 7.39; N, 15.91.

Example 5692-(Ethoxymethyl)-1-propyl-8-(tetrahydrofuran-2-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amine

Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution oftetrahydrofurfuryl bromide (330 mg, 1.99 mmol) and4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500mg, 1.66 mmol, prepared in Parts A and B of Example 566) in anhydrousDMF (20 mL). The reaction mixture was heated at 75° C. overnight,allowed to cool, and poured into deionized water (300 mL). After 30minutes of stirring, a brown precipitate formed. Sodium chloride (100 g)was added, and the resulting mixture was stirred for three hours andthen filtered. The isolated precipitate was purified by chromatographyon a HORIZON HPFC system (silica cartridge, eluting with a gradient of0-35% methanol/dichloromethane (10:90) in dichloromethane). Theresulting solid was recrystallized from acetonitrile and dried underhigh vacuum to yield 429 mg of2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-2-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amineas a fluffy, white solid, mp 178-179° C. Anal. calcd for C₂₁H₂₈N₄O₃.0.25H₂O: C, 64.84; H, 7.39; N, 14.40. Found: C, 65.03; H, 7.75; N, 14.48.

Example 5704-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ylmorpholine-4-carboxylate

Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500mg, 1.66 mmol, prepared in Parts A and B of Example 566) in anhydrousDMF (30 mL). The reaction was stirred for ten minutes, and4-morpholinecarbonyl chloride (275 mg, 1.83 g) was then added. Thereaction was stirred overnight at ambient temperature and poured intodeionized water (300 mL). The resulting mixture was stirred for one hourand then extracted with chloroform (3×100 mL). The combined organicfractions were concentrated under reduced pressure, and the resultingsolid was purified by chromatography on a HORIZON HPFC system (silicacartridge, eluting with a gradient of 0-20% CMA in chloroform). Theresulting solid was recrystallized from acetonitrile and dried undervacuum to yield 606 mg of4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ylmorpholine-4-carboxylate as a white, crystalline solid, mp 193-196° C.Anal. calcd for C₂₁H₂₇N₅O₄: C, 61.00; H, 6.58; N, 16.94. Found: C,61.01; H, 6.51; N, 17.21.

Example 5718-(2-Azepan-1-ylethoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

The preparation and purification methods described in Part C of Example566 were followed, using 1-(2-chloroethyl)azepane hydrochloride (395 mg,1.99 mmol) in lieu of 2-bromo-1-morpholin-4-ylethanone, to provide 275mg of8-(2-azepan-1-ylethoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas an off-white, crystalline solid, mp 146-148° C. Anal. calcd forC₂₄H₃₅N₅O₂: C, 67.74; H, 8.29; N, 16.46. Found: C, 67.49; H, 8.47; N,16.43.

Examples 572-645 Part A

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing a solution of7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(36 mg, 0.10 mmol, prepared as described in Example 394) andtriethylamine (0.028 mL, 0.20 mmol) in N,N-dimethylacetamide (1 mL). Thetest tubes were capped and shaken overnight at room temperature. Thesolvent was removed by vacuum centrifugation. The reaction mixtures wereseparated by solid-supported liquid-liquid extraction according to thefollowing procedure. Each sample was dissolved in chloroform (1 mL) andloaded onto diatomaceous earth that had been treated with 600 μL ofdeionized water for 20 minutes. After ten minutes, chloroform (500 μL)was added to elute the product from the diatomaceous earth into a wellof a collection plate. After an additional ten minutes, the process wasrepeated with additional chloroform (500 μL). The solvent was thenremoved by vacuum centrifugation.

Part B

Dichloromethane (1 mL) was added to test tubes containing the reactionmixtures from Part A, and the resulting mixtures were sonicated untilall solids were dissolved. The resulting solutions were cooled to 0° C.,and a solution of 1 M boron tribromide in dichloromethane (130 μL, 0.13mmol) was added to each test tube, which was maintained at 0° C. for 30minutes and then shaken on a vortexer for 2.5 hours. Methanol (0.5 mL)and 6 M aqueous hydrochloric acid (500 μL) were added to each test tube;each tube was shaken on a vortexer for 30 minutes. The volatiles wereremoved by vacuum centrifugation, and the compounds were purified byprepHPLC using the method described in Examples 376-386. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 572 None - starting materialonly

344.2116 573 Propionyl chloride

400.2354 574 Methyl chloroformate

402.2151 575 Cyclopropanecarbony chloride

412.2344 576 Butyryl chloride

414.2487 577 Isobutyryl chloride

414.2506 578 Ethyl chloroformate

416.2283 579 Methoxyacetyl chloride

402.2147 580 Cyclobutanecarbonyl chloride

426.2477 581 Isovaleryl chloride

428.2657 582 Pivaloyl chloride

428.2662 583 Cyclopentylacetyl chloride

440.2642 584 Isobutyl chloroformate

444.2586 585 Benzoyl chloride

448.2395 586 Cyclohexanecarbonyl chloride

454.2772 587 m-Toluoyl chloride

462.2513 588 o-Toluoyl chloride

462.2517 589 p-Toluoyl chloride

462.2544 590 Phenylacetyl chloride

462.2515 591 2-Fluorobenzoyl chloride

466.2296 592 4-Fluorobenzoyl chloride

466.2259 593 4-Cyanobenzoyl chloride

473.2291 594 Cinnamoyl chloride

474.2477 595 Hydrocinnamoyl chloride

476.2686 596 2-Chlorobenzoyl chloride

482.1996 597 3-Chlorobenzoyl chloride

482.1943 598 4-Chlorobenzoyl chloride

482.1992 599 Isonicotinoyl chloride hydrochloride

449.2347 600 Nicotinoyl chloride hydrochloride

449.2321 601 Picolinoyl chloride hydrochloride

449.2292 602 trans-2-Phenyl-1- Cyclopropanecarbonyl chloride

488.2635 603 4-Dimethylaminobenzoyl chloride

491.2744 604 4-Chlorophenylacetyl chloride

496.2112 605 Methanesulfonyl chloride

422.1879 606 Ethanesulfonyl chloride

436.2013 607 1-Propanesulfonyl chloride

450.2137 608 Isopropylsulfonyl chloride

450.2165 609 Dimethylsulfamoyl chloride

451.2091 610 1-Butanesulfonyl chloride

464.2363 611 Benzenesulfonyl chloride

484.2063 612 alpha-Toluenesulfonyl chloride

498.2151 613 2-Methylbenzenesulfonyl chloride

498.2155 614 4-Methylbenzenesulfonyl chloride

498.2207 615 4-Fluorobenzenesulfonyl chloride

502.1945 616 beta-Styrenesulfonyl chloride

510.2184 617 3,5-Dimethylbenzenesulfonyl chloride

512.2330 618 2-Chlorobenzenesulfonyl chloride

518.1660 619 3-Chlorobenzenesulfonyl chloride

518.1663 620 1-Naphthalenesulfonyl chloride

534.2173 621 2-Naphthalenesulfonyl chloride

534.2125 622 8-Quinolinesulfonyl chloride

535.2122 623 2- (Trifluoromethyl)benzenesulfonyl chloride

552.1940 624 3- (Trifluoromethyl)benzenesulfonyl chloride

552.1906 625 4- (Trifluoromethyl)benzenesulfonyl chloride

552.1903 626 Ethyl isocyanate

415.2448 627 N-Butyl isocyanate

443.2809 628 sec-Butyl isocyanate

443.2796 629 Cyclopentyl isocyanate

455.2740 630 Pentyl isocyanate

457.2888 631 Phenyl isocyanate

463.2447 632 m-Tolyl isocyanate

477.2644 633 o-Tolyl isocyanate

477.2613 634 p-Tolyl isocyanate

477.2592 635 2,6-Dimethylphenyl isocyanate

491.2792 636 (R)-(+)-alpha-Methylbenzyl isocyanate

491.2758 637 (S)-(−)-alpha-Methylbenzyl isocyanate

491.2758 638 2-Phenyl ethylisocyanate

491.2752 639 2-(Thien-2-yl)ethyl isocyanate

497.2327 640 4-Chlorophenyl isocyanate

497.2092 641 trans-2-Phenylcyclopropyl isocyanate

503.2795 642 N,N-Dimethylcarbamoyl chloride

415.2455 643 1-Piperidinecarbonyl chloride

455.2752 644 4-Methyl-1-piperazinecarbonyl chloride

470.2906 645 N-Methyl-N-phenylcarbamoyl chloride

477.2604

Example 6461-[4-Amino-2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

Part A

A modification of the methods described in Parts A-H of Example 2 wasused to prepare1-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol,with 3-benzyloxyaniline and 1-amino-2-methylpropan-2-ol used in lieu of4-benzyloxyaniline and propylamine, respectively. Modification on themethods described in steps M, N, and I of Example 2 were used to convert1-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olinto4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol.

Part B

A mixture of4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol(prepared as described above, 750 mg, 2.27 mmol),4-(bromoacetyl)morpholine (565 mg, 2.72 mmol), and cesium carbonate(2.22 g, 6.81 mmol) in DMF (30 mL) was heated at 75° C. overnight. Thereaction mixture was allowed to cool and was poured into water (300 mL).After 30 minutes, the solution was extracted with chloroform (6×75 mL).The organic layers were combined, dried over magnesium sulfate,filtered, and concentrated to dryness. The resulting solid was purifiedby chromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-35% methanol/dichloromethane (1:10) in dichloromethane) Theappropriate fractions were combined and concentrated to yield an offwhite solid that was slurried in boiling acetonitrile for 15 minutes.The slurry was allowed to cool with stirring. The solid was isolated byfiltration and dried to yield 797 mg of1-[4-amino-2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas an off-white solid, mp 209-211° C.

MS (ESI) m/z 458 (M+H)⁺;

Anal. calcd for C₂₃H₃N₅O₅: C, 60.38; H, 6.83; N, 15.31. Found: C, 60.25;H, 7.12; N, 15.50.

Example 6471-[4-Amino-2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

The general procedure described in Example 646 was used to convert4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol(prepared as described in Part A of Example 646, 750 mg, 2.27 mmol) into1-[4-amino-2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olwith 4-(2-chloroethyl)morpholine hydrochloride (506 mg, 2.72 mmol) usedin lieu of 4-(bromoacetyl)morpholine. The product was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-25% CMA in chloroform). The appropriate fractions were combinedand concentrated to yield a white foam that was crystallized fromacetontrile to provide 275 mg of1-[4-amino-2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas an off-white crystalline solid, mp 161-163° C.

MS (ESI) m/z 444 (M+H)⁺;

Anal. calcd for C₂₃H₃₃N₅O₄: C, 62.28; H, 7.50; N, 15.79. Found: C,62.15; H, 7.70; N, 16.01.

Example 6482-(Ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

A modification on the procedure described in Example 646 was used toconvert 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol(prepared as described in Parts A and B of Example 51) into2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine.The reaction mixture was heated overnight then was poured slowly intowater. After the mixture was stirred for 1 hour, a tan solid wasisolated by filtration and recrystallized from acetonitrile to afford2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amineas off-white crystals, mp 213° C.

MS (APCI) m/z 428 (M+H)⁺;

Anal. calcd for C₂₂H₂₉N₅O₄: C, 61.81; H, 6.84; N, 16.38. Found: C,61.61; H, 7.17; N, 16.51.

Example 6492-(Ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine

A modification on the procedure described in Example 647 was used toconvert 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol(prepared as described in Parts A and B of Example 51) into2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine.The reaction mixture was heated overnight and then was poured slowlyinto water. The mixture was stirred for 1 hour and a tan solid wasisolated by filtration and recrystallized from acetonitrile to affordoff-white crystals, mp 191-192° C.

MS (APCI) m/z 414.3 (M+H)⁺;

Anal. calcd for C₂₂H₃₁N₅O₃: C, 63.90; H, 7.56; N, 16.94. Found: C,63.76; H, 7.48; N, 16.83.

Example 6507-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine

7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride (prepared as described in Example 552, 0.100 g) wasdissolved in water (5 mL) and saturated aqueous sodium chloride (5 mL).The solution was brought to pH 13 with 50% aqueous sodium hydroxide andextracted with chloroform. The chloroform was washed successively withwater and saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was recrystallized fromacetonitrile to provide 0.065 g of7-(2-aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a white crystalline solid, mp 238° C. (decomposition).

¹H NMR (300 MHz, DMSO-d₆) δ 7.91 (d, J=9.0 Hz, 1H), 7.05 (d, J=2.6 Hz,1H), 6.92 (dd, J=9.0, 2.6 Hz, 1H), 6.32 (s, 2H), 4.38-4.37 (m, 2H), 3.99(t, J=5.8 Hz, 2H), 3.83-3.79 (m, 2H), 3.17-3.12 (m, 2H), 2.93-2.89 (m,4H), 2.12-2.01 (m, 1H), 1.58-1.38 (m, 6H), 1.36 (t, J=7.4 Hz, 3H);

MS (ESI) m/z 370.2 (M+H)⁺;

Anal. calcd for C₂₀H₂₇N₅O₂: C, 65.02; H, 7.37; N, 18.96. Found: C,64.79; H, 7.32; N, 18.96.

Example 651N-(2-{[4-Amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea

7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552),dichloromethane (10 mL), and triethylamine (0.702 mL, 5.03 mmol) werecombined and stirred for 10 minutes. Isopropyl isocyanate (0.101 mL,1.03 mmol) was added dropwise and the reaction was stirred for 16 hours.Saturated aqueous sodium carbonate (˜5 mL) was added and the reactionwas stirred for 10 minutes. The layers were separated. The organicfraction was washed with water and then concentrated under reducedpressure. The resulting crude product was purified by chromatography ona HORIZON HPFC system (silica gel, gradient elution of 2-20% CMA inchloroform) followed by recrystallization from acetonitrile to provide0.390 g ofN-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N-isopropylureaas a white solid, mp 223-225° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (d, J=9.1 Hz, 1H), 7.06 (d, J=2.6 Hz,1H), 6.92 (dd, J=9.0, 2.6 Hz, 1H), 6.38 (s, 2H), 5.95 (t, J=5.6 Hz, 1H),5.83 (d, J=7.6 Hz, 1H), 4.39-4.36 (m, 2H), 4.03 (t, J=5.8 Hz, 2H),3.84-3.79 (m, 2H), 3.73-3.62 (m, 1H), 3.45-3.36 (m, 2H), 3.21-3.09 (m,2H), 2.91 (q, J=7.4 Hz, 2H), 2.13-1.97 (m, 1H), 1.56-1.36 (m, 4H), 1.36(t, J=7.4 Hz, 3H), 1.03 (d, J=6.5 Hz, 6H);

¹³C NMR (125 MHz, DMSO-d₆) δ 157.3, 157.0, 153.7, 152.0, 146.6, 132.9,125.1, 121.2, 111.4, 109.2, 108.3, 67.2, 66.6, 49.6, 40.8, 38.7, 35.7,29.6, 23.2, 20.1, 12.1;

MS (ESI) m/z 455.2 (M+H)⁺;

Anal. calcd for C₂₄H₃₄N₆O₃.0.08H₂O.0.04CH₂Cl₂: C, 62.85; H, 7.51; N,18.29. Found: C, 62.72; H, 7.69; N, 18.16.

Example 652N-(2-{[4-Amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)acetamide

7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552),dichloromethane (10 mL), and triethylamine (0.430 mL, 3.09 mmol) werecombined and stirred for 10 minutes. Acetic anhydride (0.097 mL, 1.03mmol) was added and the reaction was stirred for an additional 16 hours.The reaction mixture was purified by chromatography on a HORIZON HPFCsystem (silica gel, gradient elution with 2-20% CMA in chloroform).Fractions containing product were combined and concentrated. Triturationof the product in acetonitrile provided 0.319 g ofN-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)acetamideas fine white crystals, mp 165-167° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (t, J=5.4 Hz, 1H), 7.92 (d, J=9.1 Hz,1H), 7.06 (d, J=2.7 Hz, 1H), 6.92 (dd, J=9.0, 2.7 Hz, 1H), 6.40 (s, 2H),4.39-4.37 (m, 2H), 4.07 (t, J=5.6 Hz, 2H), 3.84-3.79 (m, 2H), 3.45 (q,J=5.6 Hz, 2H), 3.20-3.08 (m, 2H), 2.91 (q, J=7.4 Hz, 2H), 2.13-1.98 (m,1H), 1.84 (s, 3H), 1.54-1.34 (m, 4H), 1.36 (t, J=7.4 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 169.4, 157.0, 153.7, 152.0, 146.6, 133.0,125.1, 121.2, 111.5, 109.2, 108.2, 66.6, 66.2, 49.6, 38.3, 35.7, 29.6,22.5, 20.1, 12.1;

MS (APCI) m/z 412.2 (M+H)⁺;

Anal. calcd for C₂₂H₂₉N₅O₃.0.33CH₃CN: C, 64.03; H, 7.11; N, 17.56.Found: C, 63.67; H, 7.17; N, 17.41.

Example 653N-(2-{[4-Amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)methanesulfonamide

7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminedihydrochloride (0.450 g, 0.97 mmol; prepared as in Example 552),dichloromethane (10 mL), and triethylamine (0.418 mL, 3.00 mmol) werecombined and then stirred for 10 minutes. Methanesulfonyl chloride(0.075 mL, 0.97 mmol) was added and the reaction was stirred for anadditional 16 hours. The reaction mixture was purified by chromatographyon a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA inchloroform) followed by recrystallization from acetonitrile to provide0.173 g ofN-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)methanesulfonamideas white needles.

¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (d, J=9.0 Hz, 1H), 7.31 (t, J=5.7 Hz,1H), 7.07 (d, J=2.6 Hz, 1H), 6.93 (dd, J=9.0, 2.6 Hz, 1H), 6.40 (s, 2H),4.44-4.34 (m, 2H), 4.12 (t, J=5.5 Hz, 2H), 3.87-3.77 (m, 2H), 3.44-3.35(m, 2H), 3.21-3.08 (m, 2H), 2.98 (s, 3H), 2.91 (q, J=7.4 Hz, 2H),2.12-1.98 (m, 1H), 1.55-1.34 (m, 4H), 1.36 (t, J=7.4 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 156.8, 153.8, 152.0, 146.5, 132.9, 125.1,121.3, 111.4, 109.3, 108.2, 66.8, 66.6, 49.6, 41.9, 35.7, 29.6, 20.1,12.1;

MS (APCI) m/z 448.2 (M+H)⁺;

Anal. calcd for C₂₁H₂₉N₅O₄S.1.5H₂O: C, 53.15; H, 6.80; N, 14.76; S,6.76. Found: C, 53.10; H, 6.53; N, 14.95; S, 6.75.

Example 6541-[4-Amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

Part A

tert-Butyl2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate(1.95 g, 4.12 mmol; prepared in Example 562) was slurried in 4.0 Methanolic hydrogen chloride (15 mL). The reaction was heated at 65° C.for 1.75 hours during which time the starting material dissolved and aprecipitate subsequently formed. The reaction mixture was cooled toambient temperature and the solid was filtered, washed with ethanol, anddried to provide 1.49 g of1-[4-amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-oldihydrochloride as an off-white powder.

Part B

The filtrate from Part A was evaporated and the resulting residue wasdissolved in water (5 mL) and saturated aqueous sodium chloride (5 mL).This solution was brought to pH 13 with 50% aqueous sodium hydroxide andextracted with chloroform. The chloroform was sequentially washed withwater, saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, filtered, and concentrated. Recrystallization from acetonitrileand drying provided 0.140 g of1-[4-amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas fine white crystals, mp 163-165° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=9.1 Hz, 1H), 7.03 (d, J=2.7 Hz,1H), 6.85 (dd, J=9.0, 2.7 Hz, 1H), 6.48 (s, 2H), 5.06-4.76 (m, 1H), 4.87(s, 2H), 4.62 (br s, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.50 (q, J=7.0 Hz,2H), 2.91 (t, J=5.7 Hz, 2H), 1.60 (br s, 2H), 1.16 (br s, 6H), 1.13 (t,J=7.0 Hz, 3H);

¹³C NMR (125 MHz, DMSO-d₆) δ 157.4, 152.2, 150.0, 147.1, 134.6, 124.7,122.4, 111.0, 109.3, 107.9, 70.6, 70.0, 65.2, 64.9, 54.7, 41.0, 27.6,15.0;

MS (ESI) m/z 374.22 (M+H)⁺;

Anal. calcd for C₁₉H₂₇N₅O₃.0.3H₂O: C, 60.24; H, 7.34; N, 18.49. Found:C, 60.42; H, 7.32; N, 18.76.

Example 655N-(2-{[4-Amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea

1-[4-Amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-oldihydrochloride (prepared as described in Part A of Example 654, 0.466g, 1.00 mmol), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.0mmol) were combined. The mixture was stirred for 10 minutes. Isopropylisocyanate (0.097 mL, 1.00 mmol) was added and the reaction was stirredfor 16 hours. Saturated aqueous sodium carbonate (˜8 mL) was added andthe layers were separated. The organic layer was concentrated andpurified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 2-25% CMA in chloroform). The fractions containingproduct were combined and concentrated. Trituration of the product indichloromethane, followed by filtration provided 0.319 g ofN-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylureaas an off-white powder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=9.1 Hz, 1H), 7.04 (d, J=2.6 Hz,1H), 6.86 (dd, J=9.1, 2.6 Hz, 1H), 6.51 (s, 2H), 5.95 (t, J=5.6 Hz, 1H),5.83 (d, J=7.7 Hz, 1H), 5.00-4.77 (m, 1H), 4.87 (s, 2H), 4.62 (br s,2H), 4.02 (t, J=5.5 Hz, 2H), 3.77-3.59 (m, 1H), 3.50 (q, J=7.0 Hz, 2H),3.43-3.37 (m, 2H), 1.16 (br s, 6H), 1.13 (t, J=7.0 Hz, 3H), 1.03 (d,J=6.5 Hz, 6H);

¹³C NMR (125 MHz, DMSO-d₆) δ 157.3, 157.2, 152.3, 150.0, 147.1, 134.5,124.8, 122.5, 110.8, 109.5, 108.0, 70.6, 67.2, 65.2, 64.9, 54.7, 40.8,38.7, 27.6, 23.2, 15.0;

MS (ESI) m/z 459.2 (M+H)⁺;

Anal. calcd for C₂₃H₃₄N₆O₄.2.0H₂O: C, 55.86; H, 7.75; N, 16.99. Found:C, 55.63; H, 7.56; N, 16.94.

Example 6561-[7-[(1-Acetylpiperidin-4-yl)oxy]-4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

Part A

tert-Butyl4-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate(0.580 g, 1.13 mmol; prepared in Example 563) was taken up in 4.0 Methanolic hydrogen chloride (5 mL). The reaction was heated at 65° C.for 1 hour, and then cooled to ambient temperature. The ethanol wasremoved under reduced pressure and the residue was dissolved in water (3mL) and saturated aqueous sodium chloride (7 mL). The solution wasadjusted to pH 13 with 50% aqueous sodium hydroxide and then extractedwith chloroform. The combined organic fractions were sequentially washedwith water and saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and concentrated. Trituration with acetonitrileyielded 0.467 g of1-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas an off-white solid.

Part B

1-[4-Amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol(from Part A) was slurried in dichloromethane (11 mL). Acetic anhydride(0.105 mL, 1.03 mmol) was added and the reaction was stirred for 16hours. The reaction mixture was purified by chromatography on a HORIZONHPFC system (silica gel, gradient elution with 2-25% CMA in chloroform).The resulting solid was covered with diethyl ether for one week.Filtration of the solid provided 0.130 g of1-[7-[(1-acetylpiperidin-4-yl)oxy]-4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas red-tan crystals, mp 162-164° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=9.1 Hz, 1H), 7.09 (d, J=2.5 Hz,1H), 6.87 (dd, J=9.0, 2.5 Hz, 1H), 6.47 (s, 2H), 5.04-4.77 (m, 1H), 4.86(s, 2H), 4.75-4.61 (m, 1H), 4.61 (br s, 2H), 3.98-3.82 (m, 1H),3.79-3.63 (m, 1H), 3.50 (q, J=7.0 Hz, 2H), 3.43-3.14 (m, 2H), 2.02 (s,3H), 2.02-1.87 (m, 2H), 1.74-1.44 (m, 2H), 1.16 (br s, 6H), 1.13 (t,J=7.0 Hz, 3H);

MS (APCI) m/z 456.3 (M+H)⁺;

Anal. calcd for C₂₄H₃₃N₅O₄: C, 63.28; H, 7.30; N, 15.37. Found: C,63.13; H, 7.63; N, 15.48.

Example 6572-(Methoxymethyl)-1-propyl-8-[3-(4-pyridin-2-ylpiperazin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-4-amine

Part A

8-(3-Chloropropoxy)-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-aminewas prepared using a modification on the procedure described in PartsA-E of Examples 523-550. In the work-up of Part E, the reaction mixturewas allowed to cool to room temperature and was poured into water. Apale brown solid, crude8-(3-chloropropoxy)-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine,was isolated by filtration and was used in the next step withoutpurification.

Part B

A mixture of8-(3-chloropropoxy)-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine(0.20 g, 0.55 mmol, 1 equivalent), potassium carbonate (4 equivalents),and 1-(2-pyridyl)piperazine (1.1 equivalents) in DMF (5 mL) was heatedat 70° C. overnight. The reaction mixture was allowed to cool to roomtemperature and was poured onto ice (50 g). After the mixture wasstirred for 3 hours, a brown solid was isolated by filtration. The crudeproduct was purified by chromatography on a HORIZON HPFC system (silicagel, gradient elution with 0-30% CMA in chloroform), followed byrecrystallization from acetonitrile to afford 0.065 g of2-(methoxymethyl)-1-propyl-8-[3-(4-pyridin-2-ylpiperazin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-4-amineas off white crystals, mp 196-197° C.

MS (APCI) m/z 490 (M+H)⁺;

Anal. calcd for C₂₇H₃₅N₇O₂.0.33 H₂O: C, 65.44; H, 7.25; N, 19.78. Found:C, 65.42; H, 7.28; N, 19.63.

Examples 658-661

The general method described in Example 647 can be applied to prepareExamples 658-661, whose structure and names are shown in the tablebelow, from 4-(2-chloroethyl)morpholine hydrochloride and the startingmaterials listed in the table below. The starting materials can beprepared using known methods.4-Amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol can beprepared as described in Parts A-B of Example 566.4-Amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-olcan be prepared using the methods described in Parts A-J of Example 1,using 1-amino-2-methylpropan-2-ol in lieu of isobutylamine in Part E andtriethyl orthopropionate in lieu of trimethyl orthobutyrate in Part G.4-Amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-olcan be prepared using the methods described in Parts A-J of Example 1,using 4-benzyloxyaniline in lieu of 3-benzyloxyaniline in Part A,1-amino-2-methylpropan-2-ol in lieu of isobutylamine in Part E, andtriethyl orthopropionate in lieu of trimethyl orthobutyrate in Part G. Amodification of the methods described in Parts A-H, M, N, and I ofExample 2 can be used to prepare4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-ol,with 1-amino-2-methylpropan-2-ol used in lieu of propylamine in Part E.

Starting Example Structure Name Material 658

2-(Ethoxymethyl)- 8-(2-morpholin-4- ylethoxy)-1- propyl-1H- imidazo[4,5-c]quinolin-4-amine 4-Amino-2- (ethoxymethyl)- 1-propyl-1H- imidazo[4,5-c]quinolin-8-ol 659

1-[4-Amino-2- ethyl-7-(2- morpholin-4- ylethoxy)-1H- imidazo[4,5-c]quinolin-1-yl]-2- methylpropan-2-ol 4-Amino-2- ethyl-1-(2- hydroxy-2-methylpropyl)- 1H- imidazo[4,5- c]quinolin-7-ol 660

1-[4-Amino-2- ethyl-8-(2- morpholin-4- ylethoxy)-1H- imidazo[4,5-c]quinolin-1-yl]-2- methylpropan-2-ol 4-Amino-2- ethyl-1-(2- hydroxy-2-methylpropyl)- 1H- imidazo[4,5- c]quinolin-8-ol 661

1-[4-Amino-2- (ethoxymethyl)-8- (2-morpholin-4- ylethoxy)-1H-imidazo[4,5- c]quinolin-1-yl]-2- methylpropan-2-ol 4-Amino-2-(ethoxymethyl)- 1-(2-hydroxy-2- methylpropyl)- 1H- imidazo[4,5-c]quinolin-8-ol

Examples 662-664

The general method described in Example 646 can be applied to prepareExamples 662-664, whose structure and names are shown in the tablebelow, from 4-(bromoacetyl)morpholine and the starting materials listedin the table below. The starting materials can be prepared using themethods described in Examples 658-661.

Example Structure Name Starting Material 662

1-[4-Amino-2- ethyl-7-(2- morpholin-4-yl- 2-oxoethoxy)- 1H-imidazo[4,5-c]quinolin-1-yl]- 2-methylpropan- 2-ol 4-Amino-2-ethyl- 1-(2-hydroxy-2-methylpropyl)- 1H-imidazo[4,5- c]quinolin-7-ol 663

1-[4-Amino-2- ethyl-8-(2- morpholin-4-yl- 2-oxoethoxy)- 1H-imidazo[4,5-c]quinolin-1-yl]- 2-methylpropan- 2-ol 4-Amino-2-ethyl- 1-(2-hydroxy-2-methylpropyl)- 1H-imidazo[4,5- c]quinolin-8-ol 664

1-[4-Amino-2- (ethoxymethyl)- 8-(2-morpholin- 4-yl-2- oxoethoxy)-1H-imidazo[4,5- c]quinolin-1-yl]- 2-methylpropan- 2-ol 4-Amino-2-(ethoxymethyl)- 1-(2-hydroxy-2- methylpropyl)- 1H-imidazo[4,5-c]quinolin-8-ol

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula IIa, IIb, or IIc and thefollowing R₁, R₂, and R₃ substituents, wherein each line of the table ismatched with each of Formula IIa, IIb, or IIc to represent a specificembodiment of the invention.

R₁ R₂ R₃ 2-methylpropyl methyl acetyl 2-methylpropyl methyl isobutyryl2-methylpropyl methyl (isopropylamino)carbonyl 2-methylpropyl methylmethylsulfonyl 2-methylpropyl methyl morpholin-4-ylcarbonyl2-methylpropyl ethyl acetyl 2-methylpropyl ethyl isobutyryl2-methylpropyl ethyl (isopropylamino)carbonyl 2-methylpropyl ethylmethylsulfonyl 2-methylpropyl ethyl morpholin-4-ylcarbonyl2-methylpropyl n-propyl acetyl 2-methylpropyl n-propyl isobutyryl2-methylpropyl n-propyl (isopropylamino)carbonyl 2-methylpropyl n-propylmethylsulfonyl 2-methylpropyl n-propyl morpholin-4-ylcarbonyl2-methylpropyl ethoxymethyl acetyl 2-methylpropyl ethoxymethylisobutyryl 2-methylpropyl ethoxymethyl (isopropylamino)carbonyl2-methylpropyl ethoxymethyl methylsulfonyl 2-methylpropyl ethoxymethylmorpholin-4-ylcarbonyl 2-methylpropyl 2-hydroxyethyl acetyl2-methylpropyl 2-hydroxyethyl isobutyryl 2-methylpropyl 2-hydroxyethyl(isopropylamino)carbonyl 2-methylpropyl 2-hydroxyethyl methylsulfonyl2-methylpropyl 2-hydroxyethyl morpholin-4-ylcarbonyl2-hydroxy-2-methylpropyl methyl acetyl 2-hydroxy-2-methylpropyl methylisobutyryl 2-hydroxy-2-methylpropyl methyl (isopropylamino)carbonyl2-hydroxy-2-methylpropyl methyl methylsulfonyl 2-hydroxy-2-methylpropylmethyl morpholin-4-ylcarbonyl 2-hydroxy-2-methylpropyl ethyl acetyl2-hydroxy-2-methylpropyl ethyl isobutyryl 2-hydroxy-2-methylpropyl ethyl(isopropylamino)carbonyl 2-hydroxy-2-methylpropyl ethyl methylsulfonyl2-hydroxy-2-methylpropyl ethyl morpholin-4-ylcarbonyl2-hydroxy-2-methylpropyl n-propyl acetyl 2-hydroxy-2-methylpropyln-propyl isobutyryl 2-hydroxy-2-methylpropyl n-propyl(isopropylamino)carbonyl 2-hydroxy-2-methylpropyl n-propylmethylsulfonyl 2-hydroxy-2-methylpropyl n-propyl morpholin-4-ylcarbonyl2-hydroxy-2-methylpropyl ethoxymethyl acetyl 2-hydroxy-2-methylpropylethoxymethyl isobutyryl 2-hydroxy-2-methylpropyl ethoxymethyl(isopropylamino)carbonyl 2-hydroxy-2-methylpropyl ethoxymethylmethylsulfonyl 2-hydroxy-2-methylpropyl ethoxymethylmorpholin-4-ylcarbonyl 2-hydroxy-2-methylpropyl 2-hydroxyethyl acetyl2-hydroxy-2-methylpropyl 2-hydroxyethyl isobutyryl2-hydroxy-2-methylpropyl 2-hydroxyethyl (isopropylamino)carbonyl2-hydroxy-2-methylpropyl 2-hydroxyethyl methylsulfonyl2-hydroxy-2-methylpropyl 2-hydroxyethyl morpholin-4-ylcarbonyl methylmethyl acetyl methyl methyl isobutyryl methyl methyl(isopropylamino)carbonyl methyl methyl methylsulfonyl methyl methylmorpholin-4-ylcarbonyl methyl ethyl acetyl methyl ethyl isobutyrylmethyl ethyl (isopropylamino)carbonyl methyl ethyl methylsulfonyl methylethyl morpholin-4-ylcarbonyl methyl n-propyl acetyl methyl n-propylisobutyryl methyl n-propyl (isopropylamino)carbonyl methyl n-propylmethylsulfonyl methyl n-propyl morpholin-4-ylcarbonyl methylethoxymethyl acetyl methyl ethoxymethyl isobutyryl methyl ethoxymethyl(isopropylamino)carbonyl methyl ethoxymethyl methylsulfonyl methylethoxymethyl morpholin-4-ylcarbonyl methyl 2-hydroxyethyl acetyl methyl2-hydroxyethyl isobutyryl methyl 2-hydroxyethyl (isopropylamino)carbonylmethyl 2-hydroxyethyl methylsulfonyl methyl 2-hydroxyethylmorpholin-4-ylcarbonyl n-propyl methyl acetyl n-propyl methyl isobutyryln-propyl methyl (isopropylamino)carbonyl n-propyl methyl methylsulfonyln-propyl methyl morpholin-4-ylcarbonyl n-propyl ethyl acetyl n-propylethyl isobutyryl n-propyl ethyl (isopropylamino)carbonyl n-propyl ethylmethylsulfonyl n-propyl ethyl morpholin-4-ylcarbonyl n-propyl n-propylacetyl n-propyl n-propyl isobutyryl n-propyl n-propyl(isopropylamino)carbonyl n-propyl n-propyl methylsulfonyl n-propyln-propyl morpholin-4-ylcarbonyl n-propyl ethoxymethyl acetyl n-propylethoxymethyl isobutyryl n-propyl ethoxymethyl (isopropylamino)carbonyln-propyl ethoxymethyl methylsulfonyl n-propyl ethoxymethylmorpholin-4-ylcarbonyl n-propyl 2-hydroxyethyl acetyl n-propyl2-hydroxyethyl isobutyryl n-propyl 2-hydroxyethyl(isopropylamino)carbonyl n-propyl 2-hydroxyethyl methylsulfonyl n-propyl2-hydroxyethyl morpholin-4-ylcarbonyl tetrahydro-2H-pyran-4- methylacetyl ylmethyl tetrahydro-2H-pyran-4- methyl isobutyryl ylmethyltetrahydro-2H-pyran-4- methyl (isopropylamino)carbonyl ylmethyltetrahydro-2H-pyran-4- methyl methylsulfonyl ylmethyltetrahydro-2H-pyran-4- methyl morpholin-4-ylcarbonyl ylmethyltetrahydro-2H-pyran-4- ethyl acetyl ylmethyl tetrahydro-2H-pyran-4-ethyl isobutyryl ylmethyl tetrahydro-2H-pyran-4- ethyl(isopropylamino)carbonyl ylmethyl tetrahydro-2H-pyran-4- ethylmethylsulfonyl ylmethyl tetrahydro-2H-pyran-4- ethylmorpholin-4-ylcarbonyl ylmethyl tetrahydro-2H-pyran-4- n-propyl acetylylmethyl tetrahydro-2H-pyran-4- n-propyl isobutyryl ylmethyltetrahydro-2H-pyran-4- n-propyl (isopropylamino)carbonyl ylmethyltetrahydro-2H-pyran-4- n-propyl methylsulfonyl ylmethyltetrahydro-2H-pyran-4- n-propyl morpholin-4-ylcarbonyl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl acetyl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl isobutyryl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl (isopropylamino)carbonyl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl methylsulfonyl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl morpholin-4-ylcarbonyl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl acetyl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl isobutyryl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl (isopropylamino)carbonyl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl methylsulfonyl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl morpholin-4-ylcarbonyl ylmethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula IIIa or IIIb and the followingR₁ and R₂ substituents, wherein each line of the table is matched witheach of Formula IIIa or IIIb to represent a specific embodiment of theinvention.

R₁ R₂ 2-methylpropyl methyl 2-methylpropyl ethyl 2-methylpropyl n-propyl2-methylpropyl ethoxymethyl 2-methylpropyl 2-hydroxyethyl2-hydroxy-2-methylpropyl methyl 2-hydroxy-2-methylpropyl ethyl2-hydroxy-2-methylpropyl n-propyl 2-hydroxy-2-methylpropyl ethoxymethyl2-hydroxy-2-methylpropyl 2-hydroxyethyl methyl methyl methyl ethylmethyl n-propyl methyl ethoxymethyl methyl 2-hydroxyethyl n-propylmethyl n-propyl ethyl n-propyl n-propyl n-propyl ethoxymethyl n-propyl2-hydroxyethyl tetrahydro-2H-pyran-4-ylmethyl methyltetrahydro-2H-pyran-4-ylmethyl ethyl tetrahydro-2H-pyran-4-ylmethyln-propyl tetrahydro-2H-pyran-4-ylmethyl ethoxymethyltetrahydro-2H-pyran-4-ylmethyl 2-hydroxyethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula VIa or VIb and the followingR₁, R₂, and R₃ substituents, wherein each line of the table is matchedwith each of Formula VIa or VIb to represent a specific embodiment ofthe invention.

R₁ R₂ R₃ 2-methylpropyl methyl morpholin-4-yl 2-methylpropyl methylpiperdin-1-yl 2-methylpropyl methyl pyrrolidin-1-yl 2-methylpropyl ethylmorpholin-4-yl 2-methylpropyl ethyl piperdin-1-yl 2-methylpropyl ethylpyrrolidin-1-yl 2-methylpropyl n-propyl morpholin-4-yl 2-methylpropyln-propyl piperdin-1-yl 2-methylpropyl n-propyl pyrrolidin-1-yl2-methylpropyl ethoxymethyl morpholin-4-yl 2-methylpropyl ethoxymethylpiperdin-1-yl 2-methylpropyl ethoxymethyl pyrrolidin-1-yl 2-methylpropyl2-hydroxyethyl morpholin-4-yl 2-methylpropyl 2-hydroxyethylpiperdin-1-yl 2-methylpropyl 2-hydroxyethyl pyrrolidin-1-yl2-hydroxy-2-methylpropyl methyl morpholin-4-yl 2-hydroxy-2-methylpropylmethyl piperdin-1-yl 2-hydroxy-2-methylpropyl methyl pyrrolidin-1-yl2-hydroxy-2-methylpropyl ethyl morpholin-4-yl 2-hydroxy-2-methylpropylethyl piperdin-1-yl 2-hydroxy-2-methylpropyl ethyl pyrrolidin-1-yl2-hydroxy-2-methylpropyl n-propyl morpholin-4-yl2-hydroxy-2-methylpropyl n-propyl piperdin-1-yl 2-hydroxy-2-methylpropyln-propyl pyrrolidin-1-yl 2-hydroxy-2-methylpropyl ethoxymethylmorpholin-4-yl 2-hydroxy-2-methylpropyl ethoxymethyl piperdin-1-yl2-hydroxy-2-methylpropyl ethoxymethyl pyrrolidin-1-yl2-hydroxy-2-methylpropyl 2-hydroxyethyl morpholin-4-yl2-hydroxy-2-methylpropyl 2-hydroxyethyl piperdin-1-yl2-hydroxy-2-methylpropyl 2-hydroxyethyl pyrrolidin-1-yl methyl methylmorpholin-4-yl methyl methyl piperdin-1-yl methyl methyl pyrrolidin-1-ylmethyl ethyl morpholin-4-yl methyl ethyl piperdin-1-yl methyl ethylpyrrolidin-1-yl methyl n-propyl morpholin-4-yl methyl n-propylpiperdin-1-yl methyl n-propyl pyrrolidin-1-yl methyl ethoxymethylmorpholin-4-yl methyl ethoxymethyl piperdin-1-yl methyl ethoxymethylpyrrolidin-1-yl methyl 2-hydroxyethyl morpholin-4-yl methyl2-hydroxyethyl piperdin-1-yl methyl 2-hydroxyethyl pyrrolidin-1-yln-propyl methyl morpholin-4-yl n-propyl methyl piperdin-1-yl n-propylmethyl pyrrolidin-1-yl n-propyl ethyl morpholin-4-yl n-propyl ethylpiperdin-1-yl n-propyl ethyl pyrrolidin-1-yl n-propyl n-propylmorpholin-4-yl n-propyl n-propyl piperdin-1-yl n-propyl n-propylpyrrolidin-1-yl n-propyl ethoxymethyl morpholin-4-yl n-propylethoxymethyl piperdin-1-yl n-propyl ethoxymethyl pyrrolidin-1-yln-propyl 2-hydroxyethyl morpholin-4-yl n-propyl 2-hydroxyethylpiperdin-1-yl n-propyl 2-hydroxyethyl pyrrolidin-1-yltetrahydro-2H-pyran-4- methyl morpholin-4-yl ylmethyltetrahydro-2H-pyran-4- methyl piperdin-1-yl ylmethyltetrahydro-2H-pyran-4- methyl pyrrolidin-1-yl ylmethyltetrahydro-2H-pyran-4- ethyl morpholin-4-yl ylmethyltetrahydro-2H-pyran-4- ethyl piperdin-1-yl ylmethyltetrahydro-2H-pyran-4- ethyl pyrrolidin-1-yl ylmethyltetrahydro-2H-pyran-4- n-propyl morpholin-4-yl ylmethyltetrahydro-2H-pyran-4- n-propyl piperdin-1-yl ylmethyltetrahydro-2H-pyran-4- n-propyl pyrrolidin-1-yl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl morpholin-4-yl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl piperdin-1-yl ylmethyltetrahydro-2H-pyran-4- ethoxymethyl pyrrolidin-1-yl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl morpholin-4-yl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl piperdin-1-yl ylmethyltetrahydro-2H-pyran-4- 2-hydroxyethyl pyrrolidin-1-yl ylmethyl

Compounds of the invention were found to induce or inhibit cytokinebiosynthesis when tested using the methods described below.

Cytokine Induction in Human Cells

Compounds of the invention have been found to modulate cytokinebiosynthesis by inducing the production of interferon α and/or tumornecrosis factor α when tested using the method described below.Particular examples include, but are not limited to, the compounds ofExamples 1-9, 11, 13-22, 26-37, 40-43, 45-134, 139, 143, 146-149, 151,154-156, 160, 162-201, 204-206, 209, 210, 212, 214-216, 218-220,222-224, 226-230, 233-256, 258-261, 263-278, 280-306, 308-320, 322-335,338-355, 358, 359, 361, 364-373, 376-394, 397-405, 407-409, 411-414, and418-422.

An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon (α) andtumor necrosis factor (α) (IFN and TNF, respectively) secreted intoculture media as described by Testerman et al. in “Cytokine Induction bythe Immunomodulators Imiquimod and S-27609”, Journal of LeukocyteBiology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intoEDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMC) areseparated from whole blood by density gradient centrifugation usingHISTOPAQUE-1077. Blood is diluted 1:1 with Dulbecco's Phosphate BufferedSaline (DPBS) or Hank's Balanced Salts Solution (HBSS). The PBMC layeris collected and washed twice with DPBS or HBSS and resuspended at 4×10⁶cells/mL in RPMI complete. The PBMC suspension is added to 48 well flatbottom sterile tissue culture plates (Costar, Cambridge, Mass. or BectonDickinson Labware, Lincoln Park, N.J.) containing an equal volume ofRPMI complete media containing test compound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(30-0.014 μM). The final concentration of PBMC suspension is 2×10⁶cells/mL. The plates are covered with sterile plastic lids, mixed gentlyand then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200×g) at 4° C. The cell-free culture supernatant isremoved with a sterile polypropylene pipet and transferred to sterilepolypropylene tubes. Samples are maintained at −30 to −70° C. untilanalysis. The samples are analyzed for interferon (α) by ELISA and fortumor necrosis factor (α) by ELISA or IGEN Assay.

Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

Interferon (α) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.Results are expressed in pg/mL.

Tumor necrosis factor (α) (TNF) concentration is determined using ELISAkits available from Biosource International, Camarillo, Calif.Alternately, the TNF concentration can be determined by ORIGEN M-SeriesImmunoassay and read on an IGEN M-8 analyzer from IGEN International,Gaithersburg, Md. The immunoassay uses a human TNF capture and detectionantibody pair from Biosource International, Camarillo, Calif. Resultsare expressed in pg/mL.

TNF-α Inhibition in Mouse Cells

Certain compounds of the invention may modulate cytokine biosynthesis byinhibiting production of tumor necrosis factor α (TNF-α) when testedusing the method described below. Particular examples, include but arenot limited to, the compounds of Examples 134-136, 139, 142, 143,146-151, 153, 155-161, 218-224, 226-242, 323-326, 328-333, 336, 337,355-357, and 362.

The mouse macrophage cell line Raw 264.7 is used to assess the abilityof compounds to inhibit tumor necrosis factor-α (TNF-α) production uponstimulation by lipopolysaccharide (LPS).

Single Concentration Assay: Blood Cell Preparation for Culture

Raw cells (ATCC) are harvested by gentle scraping and then counted. Thecell suspension is brought to 3×10⁵ cells/mL in RPMI with 10% fetalbovine serum (FBS). Cell suspension (100 μL) is added to 96-well flatbottom sterile tissues culture plates (Becton Dickinson Labware, LincolnPark, N.J.). The final concentration of cells is 3×10⁴ cells/well. Theplates are incubated for 3 hours. Prior to the addition of test compoundthe medium is replaced with colorless RPMI medium with 3% FBS.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. Compounds are tested at 5 μM. LPS(Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich) isdiluted with colorless RPMI to the EC₇₀ concentration as measured by adose response assay.

Incubation

A solution of test compound (1 μl) is added to each well. The plates aremixed on a microtiter plate shaker for 1 minute and then placed in anincubator. Twenty minutes later the solution of LPS (1 μL, EC₇₀concentration ˜10 ng/ml) is added and the plates are mixed for 1 minuteon a shaker. The plates are incubated for 18 to 24 hours at 37° C. in a5% carbon dioxide atmosphere.

TNF-α Analysis

Following the incubation the supernatant is removed with a pipet. TNF-αconcentration is determined by ELISA using a mouse TNF-α kit (fromBiosource International, Camarillo, Calif.). Results are expressed inpg/mL. TNF-α expression upon LPS stimulation alone is considered a 100%response.

Dose Response Assay: Blood Cell Preparation for Culture

Raw cells (ATCC) are harvested by gentle scraping and then counted. Thecell suspension is brought to 4×10⁵ cells/mL in RPMI with 10% FBS. Cellsuspension (250 μL) is added to 48-well flat bottom sterile tissuesculture plates (Costar, Cambridge, Mass.). The final concentration ofcells is 1×10⁵ cells/well. The plates are incubated for 3 hours. Priorto the addition of test compound the medium is replaced with colorlessRPMI medium with 3% FBS.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. Compounds are tested at 0.03, 0.1, 0.3, 1, 3, 5and 10 μM. LPS (Lipopolysaccaride from Salmonella typhimurium,Sigma-Aldrich) is diluted with colorless RPMI to the EC₇₀ concentrationas measured by dose response assay.

Incubation

A solution of test compound (200 μl) is added to each well. The platesare mixed on a microtiter plate shaker for 1 minute and then placed inan incubator. Twenty minutes later the solution of LPS (200 μL, EC₇₀concentration ˜10 ng/ml) is added and the plates are mixed for 1 minuteon a shaker. The plates are incubated for 18 to 24 hours at 37° C. in a5% carbon dioxide atmosphere.

TNF-α Analysis

Following the incubation the supernatant is removed with a pipet. TNF-αconcentration is determined by ELISA using a mouse TNF-α kit (fromBiosource International, Camarillo, Calif.). Results are expressed inpg/mL. TNF-α expression upon LPS stimulation alone is considered a 100%response.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. The presentinvention has been described with reference to several embodimentsthereof. The foregoing illustrative embodiments and examples have beenprovided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention is intended to be limitedonly by the claims that follow.

What is claimed is:
 1. A compound of the formula (II):

wherein: R₃ is selected from the group consisting of —Z—Y—R₄,—Z—Y—X—Y—R₄, —Z—R₅, —Z-Het, —Z-Het′-R₄, and —Z-Het′-Y—R₄; Z is selectedfrom the group consisting of alkylene, alkenylene, and alkynylene,wherein alkylene, alkenylene, and alkynylene can be optionallyinterrupted with one or more —O— groups; R is selected from the groupconsisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; n is0 or 1; R₁ is selected from the group consisting of —R₄, —X—R₄, —X—Y—R₄,—X—Y—X—Y—R₄, and —X—R₅; R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; X is selectedfrom the group consisting of alkylene, alkenylene, alkynylene, arylene,heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, andalkynylene groups can be optionally interrupted or terminated witharylene, heteroarylene, or heterocyclylene, and optionally interruptedby one or more —O— groups; Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl; R₉ is selected from the groupconsisting of hydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selectedfrom the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; Het isa non-aromatic heterocyclyl that can be unsubstituted or substituted byone or more substituents independently selected from the groupconsisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro,hydroxy, hydroxyalkyl, mercapto, cyano, aryloxy, arylalkyleneoxy,heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo; Het′ is a non-aromaticheterocyclylene that can be unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl,mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy,heteroarylalkyleneoxy, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and oxo; Q is selected from the groupconsisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—,—S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—; V is selected from thegroup consisting of —C(R₆)—, —O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W isselected from the group consisting of a bond, —C(O)—, and —S(O)₂—; and aand b are independently integers from 1 to 6 with the proviso that a+bis ≦7; with the proviso that Z can also be a bond when: R₃ is —Z-Het,—Z-Het′-R₄, or —Z-Het′-Y—R₄; or R₃ is —Z—Y₃—R₄ or —Z—Y₃—X—Y₃—R₄, and Y₃is selected from —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,—C(R₆)—N(R₈)—,

or  R₃ is —Z—R₅ and R₅ is

or a pharmaceutically acceptable salt thereof.
 2. The compound or saltof claim 1, wherein R₃ is —Z—Y—R₄ or —Z—Y—X—Y—R₄.
 3. The compound orsalt of claim 1, wherein Y is selected from the group consisting of—S(O)₀₋₂— —C(O)—, —C(O)—O—, —O—C(O)—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,

wherein Q is selected from the group consisting of a bond, —C(O)—,—C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—W—, and —S(O)₂—N(R₈)—; W is selectedfrom the group consisting of a bond, —C(O)—, and —S(O)₂—; R₆ is selectedfrom the group consisting of ═O or ═S; R₈ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and alkoxyalkylenyl; and R₁₀ isselected from the group consisting of C₄₋₆ alkylene; X is selected fromthe group consisting of alkylene, arylene, heterocyclylene,heteroarylene, and alkylene terminated with heteroarylene; and R₄ isselected from the group consisting of hydrogen, alkyl, alkenyl, aryl,arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl,aryloxyalkylenyl, heteroaryl, and heterocyclyl, wherein alkyl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of hydroxy, alkoxy, and heterocyclyl, and whereinarylalkylenyl and heteroarylalkylenyl are unsubstituted or substitutedby one or more substituents selected from the group consisting of alkyl,halogen, and alkoxy.
 4. The compound or salt of claim 1, wherein R₃ is—Z-Het, —Z-Het′-R₄, or —Z-Het′-Y—R₄.
 5. The compound or salt of claim 4,wherein Z is a bond.
 6. The compound or salt of claim 4, wherein Het orHet′ is selected from the group consisting of tetrahydropyranyl,tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, aziridinyl, azepanyl,diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl,dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl,dihydro-1H-imidazolyl, and piperazinyl.
 7. The compound or salt of claim4, wherein Het is substituted by one or more substituents selected fromthe group consisting of alkyl, hydroxyl, hydroxyalkyl,hydroxyalkyleneoxyalkylenyl, diakylamino, and heterocyclyl; Y isselected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—N(H)—, and—N(H)—C(O)—; and R₄ is selected from the group consisting of hydrogenand alkyl.
 8. The compound or salt of claim 1, wherein Z is alkylene. 9.A compound of the formula (III):

wherein: R₃₋₁ is selected from the group consisting of—Z—N(R₈)—C(R₆)—R₄,

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups; R is selected fromthe group consisting of alkyl, alkoxy, hydroxy, halogen, andtrifluoromethyl; n is 0 or 1; R₁ is selected from the group consistingof —R₄, —X—R₄, —X—Y—X—Y—R₄, and —X—R₅; R₂ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; Xis selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups; Yis selected from the group consisting of —S(O)₀₋₂—, —S(O)₂—N(R₈)—,—C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,—O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl; R₉ is selected from the groupconsisting of hydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selectedfrom the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—;V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—; and a and b are independently integers from 1to 6 with the proviso that a+b is ≦7; with the proviso that Z can alsobe a bond when R₃₋₁ is

or a pharmaceutically acceptable salt thereof.
 10. The compound or saltof claim 9, wherein R₃₋₁ is —Z—N(R₈)—C(R₆)—R₄.
 11. A compound of theformula (IV):

wherein: R₃₋₂ is selected from the group consisting of—Z—N(R₈)—S(O)₂—R₄, —Z—N(R₈)—S(O)₂—N(R₈)—R₄,

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups; R is selected fromthe group consisting of alkyl, alkoxy, hydroxy, halogen, andtrifluoromethyl; n is 0 or 1; R₁ is selected from the group consistingof —R₄, —X—Y—R₄, —X—Y—X—Y—R₄, and —X—R₅; R₂ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; Xis selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups; Yis selected from the group consisting of —S(O)₀₋₂—, —S(O)₂—N(R₈)—,—C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,—O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl; R₉ is selected from the groupconsisting of hydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selectedfrom the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—;V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—; and a and b are independently integers from 1to 6 with the proviso that a+b is ≦7; with the proviso that Z can alsobe a bond when R₃₋₂ is

or a pharmaceutically acceptable salt thereof.
 12. The compound or saltof claim 11, wherein R₃₋₂ is —Z—N(R₈)—S(O)₂—R₄.
 13. The compound or saltof claim 1, wherein n is
 0. 14. The compound or salt of claim 1, whereinR₁ is selected from the group consisting of alkyl, arylalkylenyl,aryloxyalkylenyl, hydroxyalkyl, dihydroxyalkyl, alkylsulfonylalkylenyl,—X—Y—R₄, —X—R₅, and heterocyclylalkylenyl, wherein the heterocyclyl ofthe heterocyclylalkylenyl group is optionally substituted by one or morealkyl groups; wherein X is alkylene; Y is —N(R₈)—C(O)—, —N(R₈)—S(O)₂—,—N(R₈)—C(O)—N(R₈)—, or

R₄ is alkyl, aryl, or heteroaryl; and R₅ is


15. The compound or salt of claim 14, wherein R₁ is selected from thegroup consisting of alkyl, alkoxyalkylenyl, aminoalkylenyl,hydroxyalkylenyl, dihydroxyalkylenyl and alkyl substituted by a groupselected from the group consisting of —NH—C(O)-alkyl, —NH—S(O)₂-alkyl,—NH—C(O)—NH-alkyl, —NH—C(O)—O-alkyl, phenoxy, tetrahydropyranyl,1,1-dioxidoisothiazolidin-2-yl, and 2,2-dimethyl-1,3-dioxolan-4-yl. 16.The compound or salt of claim 14, wherein R₁ is selected from the groupconsisting of 2-hydroxy-2-methylpropyl, 2-methylpropyl, propyl, ethyl,methyl, 2,3-dihydroxypropyl, 2-phenoxyethyl, 4-[(methylsulfonyl)amino]butyl, 2-methyl-2-[(methyl sulfonyl)amino]propyl,2-(acetylamino)-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl,4-{[(isopropylamino)carbonyl]amino}butyl,4-(1,1-dioxidoisothiazolidin-2-yl)butyl, tetrahydro-2H-pyran-4-ylmethyl,and (2,2-dimethyl-1,3-dioxolan-4-yl)methyl.
 17. The compound or salt ofclaim 1, wherein R₁ is R₄.
 18. The compound or salt of claim 17, whereinR₂ is selected from the group consisting of hydrogen, methyl, ethyl,propyl, butyl, ethoxymethyl, methoxymethyl, 2-methoxyethyl,hydroxymethyl, and 2-hydroxyethyl.
 19. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound or salt ofclaim 1 in combination with a pharmaceutically acceptable carrier.
 20. Amethod of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound or salt of claim 1 tothe animal.